PTPN11

Summary

PTPN11 (protein tyrosine phosphatase non-receptor type 11, HGNC:9644) is a protein-coding gene on chromosome 12q24.13, encoding Tyrosine-protein phosphatase non-receptor type 11 (Q06124). Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. It is a selective cancer dependency (DepMap: 68.2% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia.

Source: NCBI Gene 5781 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 44
• Clinical variants (ClinVar): 1,341 total — 106 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 161
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 9 cancer types
• Cancer dependency (DepMap): dependent in 68.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002834

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9644
Approved symbol	PTPN11
Name	protein tyrosine phosphatase non-receptor type 11
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Aliases	BPTP3, SH-PTP2, SHP-2, PTP2C, SHP2
Ensembl gene	ENSG00000179295
Ensembl biotype	protein_coding
OMIM	176876
Entrez	5781

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 20 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000351677, ENST00000392597, ENST00000530818, ENST00000531326, ENST00000635625, ENST00000635652, ENST00000639857, ENST00000685487, ENST00000687120, ENST00000687624, ENST00000687906, ENST00000688597, ENST00000688701, ENST00000690210, ENST00000690472, ENST00000692624, ENST00000882515, ENST00000882516, ENST00000882517, ENST00000882518, ENST00000914889, ENST00000914890, ENST00000971611, ENST00000971612, ENST00000971613, ENST00000971614, ENST00000971615

RefSeq mRNA: 4 — MANE Select: NM_002834 NM_001330437, NM_001374625, NM_002834, NM_080601

CCDS: CCDS58280, CCDS81741, CCDS9163

Canonical transcript exons

ENST00000351677 — 16 exons

Exon	Start	End
ENSE00000755331	112472944	112473040
ENSE00000755332	112477651	112477730
ENSE00000755333	112477857	112478015
ENSE00000755334	112482074	112482205
ENSE00000755335	112486475	112486629
ENSE00000755336	112488443	112488510
ENSE00000755337	112489024	112489175
ENSE00000755338	112502144	112502256
ENSE00000834910	112446276	112446398
ENSE00000834911	112504695	112504796
ENSE00000998168	112450318	112450512
ENSE00001128788	112455950	112456063
ENSE00001128794	112454564	112454680
ENSE00001128803	112453195	112453387
ENSE00001202658	112418947	112419125
ENSE00001397891	112505825	112509918

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6163 / max 265.9175, expressed in 1803 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128075	12.9547	1773
128074	5.9012	1644
128076	1.7603	1019

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	99.32	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.30	gold quality
globus pallidus	UBERON:0001875	99.25	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.01	gold quality
visceral pleura	UBERON:0002401	98.96	gold quality
parietal pleura	UBERON:0002400	98.91	gold quality
subthalamic nucleus	UBERON:0001906	98.89	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.80	gold quality
inferior olivary complex	UBERON:0002127	98.79	gold quality
medulla oblongata	UBERON:0001896	98.77	gold quality
choroid plexus epithelium	UBERON:0003911	98.75	gold quality
lateral globus pallidus	UBERON:0002476	98.74	gold quality
substantia nigra pars compacta	UBERON:0001965	98.72	gold quality
CA1 field of hippocampus	UBERON:0003881	98.72	gold quality
cranial nerve II	UBERON:0000941	98.70	gold quality
endothelial cell	CL:0000115	98.69	gold quality
inferior vagus X ganglion	UBERON:0005363	98.65	gold quality
pleura	UBERON:0000977	98.64	gold quality
tibia	UBERON:0000979	98.61	gold quality
superior vestibular nucleus	UBERON:0007227	98.61	gold quality
postcentral gyrus	UBERON:0002581	98.51	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.45	gold quality
parietal lobe	UBERON:0001872	98.44	gold quality
corpus callosum	UBERON:0002336	98.40	gold quality
entorhinal cortex	UBERON:0002728	98.40	gold quality
heart right ventricle	UBERON:0002080	98.36	gold quality
tendon of biceps brachii	UBERON:0008188	98.31	gold quality
orbitofrontal cortex	UBERON:0004167	98.24	gold quality
blood vessel layer	UBERON:0004797	98.24	gold quality
saphenous vein	UBERON:0007318	98.22	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, PPARG

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 68.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• upon translocation, CagA perturbs cellular functions by deregulating SHP-2 (PMID:11743164)
• SHP-2 modulates phosphorylation of PDGF receptors, thereby controls RasGTP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors (PMID:11896619)
• Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation (PMID:11956229)
• interacts with siglec-11 (PMID:11986327)
• PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. (PMID:11992261)
• Band 3 is an anchor protein for and a target for SHP-2 tyrosine phosphatase in human erythrocytes. (PMID:12070037)
• PTPN11 mutations are responsible for Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11. (PMID:12161469)
• Some PTPN11 mutations (e.g., Y279C) are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or cafe au lait spots (LEOPARD syndrome). (PMID:12161596)
• SHP-2 is a dual-specificity protein phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues and plays an important role in modulating STAT function in gene regulation (PMID:12270932)
• Mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome and confirm that the disease exhibits both allelic and locus heterogeneity. (PMID:12325025)
• Results indicate that Gab1 and SHP-2 promote the undifferentiated epidermal cell state by facilitating Ras/MAPK signaling. (PMID:12370245)
• absence of mutation in cases of cardiofaciocutaneous syndrome (PMID:12384786)
• activation state of alphaVbeta3 integrin is an important regulator of the duration of insulin-like growth factor I receptor phosphorylation and this regulation is mediated through changes in the subcellular localization of SHP-2 (PMID:12399420)
• These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130. (PMID:12403768)
• We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. (PMID:12529707)
• SHP-2 may function as an adaptor molecule downstream of the the prolactin receptor and highlight a new recruitment mechanism of SHP-2 substrates. (PMID:12531430)
• SHP2 positively regulates IL-2 induced MAPK activation in malignant T cells. SHP2 may not be involved in the activation of Stat3 or Stat5 in cutaneous T-cell lymphoma cells. (PMID:12543077)
• The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa (PMID:12552462)
• During platelet activation, a functionally active complex between SHIP-2, filamin, actin, and GPIb-IX-V may orchestrate the localized hydrolysis of PtdIns(3,4,5)P3 and thereby regulate cortical and submembraneous actin. (PMID:12676785)
• SHP-2 catalytic activity plays a direct role in the inhibitory function of killer cell Ig-like receptors, and SHP-2 inhibits NK cell activation in concert with SHP-1. (PMID:12707331)
• Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. (PMID:12717436)
• PTPN11 mutations do not cause Costello syndrome (PMID:12752577)
• Required for RetM918T-induced Akt activation. Downstream mediator of mutated receptors RetC634Y and RetM918T. Acts as limiting factor in Ret-associated endocrine tumors, in neoplastic syndromes multiple endocrine neoplasia types 2A and 2B. (PMID:12959980)
• SHP-2 has a role as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways (PMID:14522994)
• SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies (PMID:14644997)
• results reveal that Gab1 protein recruits SHP2 protein tyrosine phosphatase to dephosphorylate paxillin (PMID:14665621)
• SHP-2/Gab1 association is critical for linking EGFR to NF-kappaB transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells (PMID:14701753)
• wider role of PTPN11 lesions in leukemogenesis, but also a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion. (PMID:14982869)
• A missense mutation (836A–>G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members (PMID:14991917)
• inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phosphatases can block inhibition by KIR3DL1. (PMID:15187115)
• PTPN11 mutations account for approximately 40% of Noonan syndrome patients. Type of cardiovascular lesions and occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients. (PMID:15240615)
• In contrast to childood MDS and AML, mutations in PTPN11 make little or no contribution to the pathogenesis of adult MDS and AML. (PMID:15282682)
• PTPN11 missense mutations are associated with acute myeloid leukemia (PMID:15385933)
• Aspartate 61 plays a major role for proper down-regulation of the protein tyrosine phosphatase activity of SHP-2; the D61Del variant is predicted to have lower stability of the D’EF loop of the N-terminal SH2 domain compared to the wild-type (PMID:15521065)
• Most common mutation was A922G in exon 8. In exon 4 a mutation encoded C-SH2 domain of PTPN11 gene in two patients. A 218C–>T mutation was found in exon 3 in a patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia. (PMID:15539800)
• SHP2 binds CAT and acquires a hydrogen peroxide-resistant phosphatase activity via integrin-signaling. (PMID:15556604)
• SHP-2 has a role in regulating IL-1-induced Ca2+ flux and ERK activation via phosphorylation of PLCgamma1 (PMID:15563458)
• data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GM-CSF due to hyperactivation of the Ras signaling axis (PMID:15644411)
• Tyr-992 and Tyr-1173 are required for phosphorylation of the epidermal growth factor receptor by ionizing radiation and modulation by SHP2 (PMID:15708852)
• Mutations are rare in adult myelodysplastic syndromes and chronic myelomonocytic leukemia. (PMID:15725481)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptpn11a	ENSDARG00000020334
mus_musculus	Ptpn11	ENSMUSG00000043733
rattus_norvegicus	Ptpn11	ENSRNOG00000030124

Paralogs (35): PTPRN (ENSG00000054356), PTPRU (ENSG00000060656), PTPN3 (ENSG00000070159), PTPN21 (ENSG00000070778), PTPN18 (ENSG00000072135), PTPN23 (ENSG00000076201), PTPRH (ENSG00000080031), PTPRC (ENSG00000081237), PTPN4 (ENSG00000088179), PTPRS (ENSG00000105426), PTPRZ1 (ENSG00000106278), PTPN5 (ENSG00000110786), PTPN6 (ENSG00000111679), PTPRB (ENSG00000127329), PTPN12 (ENSG00000127947), PTPRE (ENSG00000132334), PTPRA (ENSG00000132670), PTPN22 (ENSG00000134242), PTPRF (ENSG00000142949), PTPN7 (ENSG00000143851), PTPRG (ENSG00000144724), PTPRJ (ENSG00000149177), PTPRO (ENSG00000151490), PTPN14 (ENSG00000152104), PTPRK (ENSG00000152894), PTPRR (ENSG00000153233), PTPRD (ENSG00000153707), PTPRN2 (ENSG00000155093), PTPN13 (ENSG00000163629), PTPN9 (ENSG00000169410), PTPRM (ENSG00000173482), PTPN2 (ENSG00000175354), PTPRT (ENSG00000196090), PTPN1 (ENSG00000196396), PTPN20 (ENSG00000204179)

Protein

Protein identifiers

Tyrosine-protein phosphatase non-receptor type 11 — Q06124 (reviewed: Q06124)

Alternative names: Protein-tyrosine phosphatase 1D, Protein-tyrosine phosphatase 2C, SH-PTP2, SH-PTP3

All UniProt accessions (9): A0A0U1RRI0, A0A1W2PPU4, A0A8I5KRZ3, A0A8I5KVS6, A0A8I5KW48, A0A8I5QJ58, A0A8I5QL30, Q06124, H0YF12

UniProt curated annotations — full annotation on UniProt →

Function. Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Positively regulates MAPK signal transduction pathway. Dephosphorylates GAB1, ARHGAP35 and EGFR. Dephosphorylates ROCK2 at ‘Tyr-722’ resulting in stimulation of its RhoA binding activity. Dephosphorylates CDC73. Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification. Dephosphorylates tyrosine-phosphorylated NEDD9/CAS-L. Acts as an effector of PDCD1-mediated inhibition of T-cell response: recruited by phosphorylated PDCD1, mediating dephosphorylation of key T-cell receptor (TCR) proximal signaling molecules, leading to TCR signaling inhibition.

Subunit / interactions. Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1. Interacts with MILR1 (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2. Interacts with PDGFRA (tyrosine phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts with GAB2. Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. Interacts with ROS1; mediates PTPN11 phosphorylation. Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity. Interacts with GAREM1 isoform 1 (tyrosine phosphorylated); the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation. Interacts with CDC73. Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent. Interacts with MPIG6B (via ITIM motif). Interacts with SIGLEC10. Interacts with FCRL3 (via phosphorylated ITIM motifs). Interacts with CLEC12B (via ITIM motif); this interaction triggers dephosphorylation and activation of PTPN11. Interacts (via SH2 domains) with NEDD9/CAS-L; the interaction is enhanced when NEDD9/CAS-L is tyrosine phosphorylated.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed, with highest levels in heart, brain, and skeletal muscle.

Post-translational modifications. Phosphorylated on Tyr-542 and Tyr-580 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated upon activation of the receptor-type kinase PDGFRA. Phosphorylated by activated PDGFRB.

Disease relevance. LEOPARD syndrome 1 (LPRD1) [MIM:151100] A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 1 (NS1) [MIM:163950] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. Some patients with NS1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villonodular synovitis (PVNS) when occurring in the jaw or joints. The disease is caused by variants affecting the gene represented in this entry. Mutations in PTPN11 account for more than 50% of the cases. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785] An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. The disease is caused by variants affecting the gene represented in this entry. Metachondromatosis (MC) [MIM:156250] A skeletal disorder with radiologic features of both multiple exostoses and Ollier disease, characterized by the presence of exostoses, commonly of the bones of the hands and feet, and enchondromas of the metaphyses of long bones and iliac crest. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme. The SH2 domains recognize and bind PDCD1 phosphorylated at ‘Tyr-248’.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q06124-2	1, PTP2C	yes
Q06124-1	2, PTP2Ci
Q06124-3	3

RefSeq proteins (4): NP_001317366, NP_001361554, NP_002825, NP_542168 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000242	PTP_cat	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR000980	SH2	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR012152	Tyr_Pase_non-rcpt_typ-6/11	Family
IPR016130	Tyr_Pase_AS	Active_site
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF00102

Enzyme classification (BRENDA):

• EC 3.1.3.48 — protein-tyrosine-phosphatase (BRENDA: 59 organisms, 501 substrates, 1326 inhibitors, 270 Km, 165 kcat entries)

Substrate kinetics (BRENDA)

70 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-NITROPHENYL PHOSPHATE	0.0008–148	84
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.0039–0.862	27
P-NITROPHENYL PHOSPHATE	0.0024–10	20
DADEPYLIPQQG	0.0003–0.1	12
PHOSPHOTYROSINE	0.012–30	11
LYSOZYME	0.0003–0.012	5
MYELIN BASIC PROTEIN	0.0001–0.022	5
ACETYL-DADEPY-NH2	0.0228–0.219	4
ACETYL-DADEPYL-NH2	1.1–97.5	4
4,6,8-TRIMETHYL-2-OXO-2H-CHROMEN-7-YL DIHYDROGEN	0.02–0.156	3
SASASPYSASA	0.53–2.3	3
1-NAPHTHYL PHOSPHATE	1.19–1.88	2
3,6-FLUORESCEIN DIPHOSPHATE	15–19	2
4-METHYLUMBELLIFERYL PHOSPHATE	0.953–2.41	2
BOVINE SERUM ALBUMIN	0.0001–0.0003	2

Catalyzed reactions (Rhea), 1 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)

UniProt features (154 total): sequence variant 61, strand 44, helix 21, modified residue 5, turn 4, binding site 3, splice variant 3, domain 3, mutagenesis site 3, sequence conflict 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

115 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9EIK	X-RAY DIFFRACTION	1.25
3ZM1	X-RAY DIFFRACTION	1.4
4JMG	X-RAY DIFFRACTION	1.4
7PPM	X-RAY DIFFRACTION	1.48
3ZM0	X-RAY DIFFRACTION	1.5
3ZM2	X-RAY DIFFRACTION	1.5
3ZM3	X-RAY DIFFRACTION	1.5
7PPL	X-RAY DIFFRACTION	1.53
9EIC	X-RAY DIFFRACTION	1.58
9EHD	X-RAY DIFFRACTION	1.59
3B7O	X-RAY DIFFRACTION	1.6
4RDD	X-RAY DIFFRACTION	1.6
5EHR	X-RAY DIFFRACTION	1.7
9MQ5	X-RAY DIFFRACTION	1.7
9EHA	X-RAY DIFFRACTION	1.71
9Z70	X-RAY DIFFRACTION	1.73
5DF6	X-RAY DIFFRACTION	1.78
3TKZ	X-RAY DIFFRACTION	1.8
6CMP	X-RAY DIFFRACTION	1.8
7RCT	X-RAY DIFFRACTION	1.8
9MUQ	X-RAY DIFFRACTION	1.8
9Y5X	X-RAY DIFFRACTION	1.8
8B5Y	X-RAY DIFFRACTION	1.83
8S07	X-RAY DIFFRACTION	1.83
9EH9	X-RAY DIFFRACTION	1.83
8S0O	X-RAY DIFFRACTION	1.83
8S0K	X-RAY DIFFRACTION	1.84
8T6G	X-RAY DIFFRACTION	1.84
5EHP	X-RAY DIFFRACTION	1.85
5I6V	X-RAY DIFFRACTION	1.87

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06124-F1	86.34	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 459 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (3): 506; 425; 459–465

Post-translational modifications (5): 2, 62, 66, 542, 580

Mutagenesis-validated functional residues (3):

Position	Phenotype
32	abolished binding to tyrosine-phosphorylated pdcd1 when associated with a-138.
138	abolished binding to tyrosine-phosphorylated pdcd1 when associated with a-32.
459	abolishes phosphatase activity. enhances interaction with nedd9.

Function

Pathways and Gene Ontology

Reactome pathways

52 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-109704	PI3K Cascade
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-112411	MAPK1 (ERK2) activation
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-1170546	Prolactin receptor signaling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-180292	GAB1 signalosome
R-HSA-186763	Downstream signal transduction
R-HSA-210990	PECAM1 interactions
R-HSA-210993	Tie2 Signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2586552	Signaling by Leptin
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-389948	Co-inhibition by PD-1
R-HSA-391160	Signal regulatory protein family interactions
R-HSA-418886	Netrin mediated repulsion signals
R-HSA-432142	Platelet sensitization by LDL
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654710	PI-3K cascade:FGFR3
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654726	Negative regulation of FGFR1 signaling

MSigDB gene sets: 1080 (showing top): PID_SHP2_PATHWAY, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, REACTOME_INTERLEUKIN_6_SIGNALING, BROWNE_HCMV_INFECTION_4HR_UP, MODULE_97, GOBP_HINDBRAIN_DEVELOPMENT, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CARBOHYDRATE_TRANSPORT

GO Biological Process (68): DNA damage checkpoint signaling (GO:0000077), triglyceride metabolic process (GO:0006641), epidermal growth factor receptor signaling pathway (GO:0007173), integrin-mediated signaling pathway (GO:0007229), axonogenesis (GO:0007409), brain development (GO:0007420), heart development (GO:0007507), fibroblast growth factor receptor signaling pathway (GO:0008543), hormone-mediated signaling pathway (GO:0009755), cytokine-mediated signaling pathway (GO:0019221), cerebellar cortex formation (GO:0021697), platelet formation (GO:0030220), T cell costimulation (GO:0031295), positive regulation of lipopolysaccharide-mediated signaling pathway (GO:0031666), negative regulation of chondrocyte differentiation (GO:0032331), negative regulation of type I interferon production (GO:0032480), microvillus organization (GO:0032528), positive regulation of interferon-beta production (GO:0032728), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of cell adhesion mediated by integrin (GO:0033629), multicellular organism growth (GO:0035264), organ growth (GO:0035265), peptidyl-tyrosine dephosphorylation (GO:0035335), megakaryocyte development (GO:0035855), atrioventricular canal development (GO:0036302), ERBB signaling pathway (GO:0038127), negative regulation of T cell proliferation (GO:0042130), vasodilation (GO:0042311), hormone metabolic process (GO:0042445), glucose homeostasis (GO:0042593), regulation of protein-containing complex assembly (GO:0043254), positive regulation of ossification (GO:0045778), positive regulation of mitotic cell cycle (GO:0045931), positive regulation of D-glucose import across plasma membrane (GO:0046326), positive regulation of insulin receptor signaling pathway (GO:0046628), negative regulation of insulin secretion (GO:0046676), regulation of protein export from nucleus (GO:0046825), positive regulation of hormone secretion (GO:0046887), platelet-derived growth factor receptor signaling pathway (GO:0048008), neurotrophin TRK receptor signaling pathway (GO:0048011)

GO Molecular Function (15): phosphotyrosine residue binding (GO:0001784), phosphoprotein phosphatase activity (GO:0004721), protein tyrosine phosphatase activity (GO:0004725), non-membrane spanning protein tyrosine phosphatase activity (GO:0004726), insulin receptor binding (GO:0005158), protein kinase binding (GO:0019901), signaling receptor complex adaptor activity (GO:0030159), receptor tyrosine kinase binding (GO:0030971), cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), peptide hormone receptor binding (GO:0051428), molecular adaptor activity (GO:0060090), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), focal adhesion (GO:0005925), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-20 pathways:

Category	Pathways
RAF-independent MAPK1/3 activation	2
Cell surface interactions at the vascular wall	2
Regulation of T cell activation by CD28 family	2
Interleukin-6 family signaling	1
IRS-mediated signalling	1
Platelet activation, signaling and aggregation	1
Cytokine Signaling in Immune system	1
Intracellular signaling by second messengers	1
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by EGFR	1
Signaling by PDGF	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor binding	3
cellular anatomical structure	3
cell surface receptor signaling pathway	2
animal organ development	2
anatomical structure formation involved in morphogenesis	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
acylglycerol metabolic process	1
ERBB signaling pathway	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
central nervous system development	1
head development	1
circulatory system development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
signal transduction	1
cellular response to hormone stimulus	1
cellular response to cytokine stimulus	1
cerebellar cortex morphogenesis	1
myeloid cell differentiation	1
platelet morphogenesis	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
positive regulation of response to biotic stimulus	1
positive regulation of signal transduction	1
lipopolysaccharide-mediated signaling pathway	1
regulation of lipopolysaccharide-mediated signaling pathway	1
positive regulation of response to external stimulus	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1

Protein interactions and networks

STRING

4513 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTPN11	SOS1	Q07889	997
PTPN11	SIRPA	P78324	997
PTPN11	GAB2	Q9UQC2	995
PTPN11	S100A8	P05109	995
PTPN11	FRS2	Q8WU20	995
PTPN11	GAB1	Q13480	992
PTPN11	EGFR	P00533	991
PTPN11	GRB2	P29354	990
PTPN11	IRS1	P35568	987
PTPN11	BTLA	Q7Z6A9	986
PTPN11	FRS3	O43559	984
PTPN11	CTLA4	P16410	984
PTPN11	PRPF19	Q9UMS4	982
PTPN11	SHC1	P29353	982
PTPN11	SRC	P12931	980

IntAct

702 interactions, top by confidence:

A	B	Type	Score
EGFR	GRB2	psi-mi:“MI:0914”(association)	0.980
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
PTPN11	GAB1	psi-mi:“MI:0915”(physical association)	0.960
GAB1	PTPN11	psi-mi:“MI:0915”(physical association)	0.960
GRB2	PTPN11	psi-mi:“MI:0915”(physical association)	0.910
PTPN11	GRB2	psi-mi:“MI:0914”(association)	0.910
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
PTPN11	EGFR	psi-mi:“MI:0915”(physical association)	0.860
EGFR	PTPN11	psi-mi:“MI:2364”(proximity)	0.860
THEMIS	GRB2	psi-mi:“MI:0914”(association)	0.840
PTPN11	IGF1R	psi-mi:“MI:0915”(physical association)	0.770
PTK2	EGFR	psi-mi:“MI:0914”(association)	0.750
PTPN11	TRIM32	psi-mi:“MI:0915”(physical association)	0.740
TRIM32	PTPN11	psi-mi:“MI:0915”(physical association)	0.740
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
CD244	SH2D1B	psi-mi:“MI:0914”(association)	0.690
PTK2	PTPN11	psi-mi:“MI:0915”(physical association)	0.690
PTPN11	PTK2	psi-mi:“MI:0914”(association)	0.690
PTK2	PTPN11	psi-mi:“MI:0203”(dephosphorylation reaction)	0.690
PTPN11	PTK2	psi-mi:“MI:0915”(physical association)	0.690

BioGRID (794): RPIA (Two-hybrid), TRIM32 (Two-hybrid), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Affinity Capture-MS), PTPN11 (Co-fractionation), PTPN11 (Co-fractionation), GRB2 (Affinity Capture-Western), PTPN11 (Reconstituted Complex), LNX1 (Two-hybrid)

ESM2 similar proteins: A1L1L3, B3NKK1, B4IMC3, B4NSS9, G5EC24, G5EGA9, G5EGU2, H2KZM6, H2KZW3, O08617, O55082, P04157, P06800, P08575, P18052, P18475, P28192, P29349, P29351, P34138, P34337, P34442, P35235, P41499, P42083, P42159, P81718, Q05209, Q06124, Q10656, Q15256, Q20402, Q22712, Q4JDL3, Q5I124, Q5I128, Q5I137, Q5I138, Q5I139, Q5I141

Diamond homologs: A0A6I8TCE0, A1L1L3, A2ALK8, A4IFW2, B0V2N1, B0X4T2, B1AUH1, B2GV87, B2RU80, B3DK56, B9EKR1, E9Q0N2, E9Q612, F1NWE3, G5EC24, G5EGJ9, H2KZM6, O02695, O08617, O13016, O35239, O55082, P06800, P16620, P17706, P18031, P18052, P18433, P20417, P23467, P23468, P23469, P23470, P23471, P26045, P28191, P29074, P29350, P29351, P29352

SIGNOR signaling

77 interactions.

A	Effect	B	Mechanism
PTPN11	down-regulates	GAB2	dephosphorylation
PTPN11	down-regulates	SPRY1	dephosphorylation
PTPN11	down-regulates	CTNNA1	dephosphorylation
PTPN11	down-regulates	PTK2	dephosphorylation
PTPN11	up-regulates	HOXA10	dephosphorylation
PTPN11	up-regulates	MAP3K5	dephosphorylation
PTPN11	down-regulates	GAB1	dephosphorylation
PTPN11	“down-regulates activity”	GAB1	dephosphorylation
PTPN11	“up-regulates quantity by stabilization”	JAK2	dephosphorylation
PTPN11	“up-regulates activity”	SRC	dephosphorylation
PTPN11	“down-regulates activity”	STAT1	dephosphorylation
PRKCB	unknown	PTPN11	phosphorylation
PRKCH	unknown	PTPN11	phosphorylation
PRKCA	unknown	PTPN11	phosphorylation
PTPN11	“up-regulates activity”	HRAS	dephosphorylation
PTPN11	“up-regulates activity”	NRAS	dephosphorylation
PTPN11	“up-regulates activity”	KRAS	dephosphorylation
HOOK1	“down-regulates activity”	PTPN11	binding
“8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid”	“down-regulates activity”	PTPN11	“chemical inhibition”
PTPN11	“up-regulates activity”	GRB2	binding
PTPN11	“up-regulates activity”	ERK1/2
LEPR	“up-regulates activity”	PTPN11	binding
PTPN11	“down-regulates activity”	α-Catenin	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 191 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PI3K events in ERBB2 signaling	6	30.5×	2e-06
Signaling by ERBB2 ECD mutants	6	30.5×	2e-06
Constitutive Signaling by EGFRvIII	5	27.0×	3e-05
Signaling by ERBB2 KD Mutants	8	25.6×	6e-08
Signal regulatory protein family interactions	5	25.4×	4e-05
SHC1 events in ERBB2 signaling	7	25.2×	6e-07
Signaling by ERBB2 TMD/JMD mutants	7	25.2×	6e-07
GRB2 events in ERBB2 signaling	5	24.0×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	10	24.9×	3e-09
regulation of ERK1 and ERK2 cascade	6	20.6×	5e-05
positive regulation of protein targeting to membrane	6	19.9×	6e-05
cell surface receptor protein tyrosine kinase signaling pathway	19	19.5×	2e-16
positive regulation of blood vessel endothelial cell migration	7	16.2×	3e-05
epidermal growth factor receptor signaling pathway	11	16.1×	2e-08
ephrin receptor signaling pathway	6	12.2×	7e-04
protein autophosphorylation	14	12.0×	4e-09

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 9 cancer types — ALL, AML, CLLSLL, COADREAD, GBM, LGGNOS, NBL, PAST, PCM.

Clinical variants and AI predictions

ClinVar

1341 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	106
Likely pathogenic	54
Uncertain significance	525
Likely benign	434
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070485	NC_000012.11:g.(?112915449)(112915825_?)del	Pathogenic
1072028	NM_002834.5(PTPN11):c.1075G>T (p.Glu359Ter)	Pathogenic
1201246	NM_002834.5(PTPN11):c.855T>A (p.Phe285Leu)	Pathogenic
1216064	NM_002834.5(PTPN11):c.1247G>A (p.Trp416Ter)	Pathogenic
13324	NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser)	Pathogenic
13326	NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)	Pathogenic
13327	NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser)	Pathogenic
13328	NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)	Pathogenic
13329	NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp)	Pathogenic
13330	NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly)	Pathogenic
13331	NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)	Pathogenic
13332	NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr)	Pathogenic
13333	NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)	Pathogenic
13334	NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile)	Pathogenic
13335	NM_002834.5(PTPN11):c.854T>C (p.Phe285Ser)	Pathogenic
13337	NM_002834.5(PTPN11):c.227A>T (p.Glu76Val)	Pathogenic
13339	NM_002834.5(PTPN11):c.227A>C (p.Glu76Ala)	Pathogenic
13342	NM_002834.5(PTPN11):c.1381G>A (p.Ala461Thr)	Pathogenic
13343	NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala)	Pathogenic
13344	NM_002834.5(PTPN11):c.1529A>C (p.Gln510Pro)	Pathogenic
13346	NM_002834.5(PTPN11):c.179_181del (p.Gly60del)	Pathogenic
13347	NM_002834.5(PTPN11):c.514_524del (p.Ile172fs)	Pathogenic
13348	NM_002834.5(PTPN11):c.412C>T (p.Arg138Ter)	Pathogenic
1370287	NC_000012.11:g.(?112910728)(112910864_?)del	Pathogenic
1374451	NM_002834.5(PTPN11):c.220_221dup (p.Leu74fs)	Pathogenic
1435208	NM_002834.5(PTPN11):c.18del (p.Trp6fs)	Pathogenic
162464	NM_002834.5(PTPN11):c.1508G>C (p.Gly503Ala)	Pathogenic
181495	NM_002834.5(PTPN11):c.211T>G (p.Phe71Val)	Pathogenic
1901747	NM_002834.5(PTPN11):c.1534C>T (p.Arg512Ter)	Pathogenic
2012413	NM_002834.5(PTPN11):c.971_972insGAGTTACAAGTGCAACAATTCAAAG (p.Lys325fs)	Pathogenic

SpliceAI

2348 predictions. Top by Δscore:

Variant	Effect	Δscore
12:112419125:GGT:G	donor_loss	1.0000
12:112419126:GTG:G	donor_loss	1.0000
12:112419127:T:A	donor_loss	1.0000
12:112446273:AAGAT:A	acceptor_gain	1.0000
12:112446274:A:G	acceptor_gain	1.0000
12:112446274:AGAT:A	acceptor_gain	1.0000
12:112446275:G:GG	acceptor_gain	1.0000
12:112446275:GAT:G	acceptor_gain	1.0000
12:112446275:GATG:G	acceptor_gain	1.0000
12:112450290:T:TA	acceptor_gain	1.0000
12:112450303:A:AG	acceptor_gain	1.0000
12:112450303:AAT:A	acceptor_gain	1.0000
12:112450303:AATG:A	acceptor_gain	1.0000
12:112450304:A:G	acceptor_gain	1.0000
12:112450304:AT:A	acceptor_gain	1.0000
12:112450304:ATG:A	acceptor_gain	1.0000
12:112450305:T:A	acceptor_gain	1.0000
12:112450306:G:A	acceptor_gain	1.0000
12:112450511:AGGT:A	donor_loss	1.0000
12:112450513:G:A	donor_loss	1.0000
12:112450514:T:G	donor_loss	1.0000
12:112453355:TCTA:T	donor_gain	1.0000
12:112453385:CAG:C	donor_loss	1.0000
12:112453387:GG:G	donor_loss	1.0000
12:112453388:G:C	donor_loss	1.0000
12:112453389:T:A	donor_loss	1.0000
12:112454558:T:TA	acceptor_gain	1.0000
12:112454563:G:GT	acceptor_loss	1.0000
12:112454677:GCAG:G	donor_gain	1.0000
12:112454678:CAG:C	donor_loss	1.0000

AlphaMissense

3949 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:112446277:T:A	W6R	1.000
12:112446277:T:C	W6R	1.000
12:112446280:T:C	F7L	1.000
12:112446281:T:C	F7S	1.000
12:112446282:T:A	F7L	1.000
12:112446282:T:G	F7L	1.000
12:112446283:C:G	H8D	1.000
12:112446298:G:C	G13R	1.000
12:112446298:G:T	G13C	1.000
12:112446299:G:A	G13D	1.000
12:112446307:G:C	A16P	1.000
12:112446320:T:A	L20Q	1.000
12:112446320:T:C	L20P	1.000
12:112446331:G:A	G24R	1.000
12:112446331:G:C	G24R	1.000
12:112446332:G:A	G24E	1.000
12:112446346:T:C	F29L	1.000
12:112446347:T:C	F29S	1.000
12:112446348:T:A	F29L	1.000
12:112446348:T:G	F29L	1.000
12:112446350:T:C	L30S	1.000
12:112446350:T:G	L30W	1.000
12:112446353:C:A	A31E	1.000
12:112446355:A:T	R32W	1.000
12:112446356:G:C	R32T	1.000
12:112446356:G:T	R32M	1.000
12:112446357:G:C	R32S	1.000
12:112446357:G:T	R32S	1.000
12:112446361:A:C	S34R	1.000
12:112446362:G:T	S34I	1.000

dbSNP variants (sampled 300 via entrez): RS1000047335 (12:112485910 G>A), RS1000084429 (12:112485684 A>G), RS1000109532 (12:112468318 C>T), RS1000114543 (12:112430375 T>C), RS1000131437 (12:112479412 G>A), RS1000131770 (12:112430954 G>A,T), RS1000215138 (12:112498962 T>C), RS1000217578 (12:112449746 G>A,T), RS1000225485 (12:112444349 T>C), RS1000276468 (12:112510345 C>G,T), RS1000308020 (12:112423710 C>T), RS1000332876 (12:112471343 G>A,C), RS1000338919 (12:112424095 T>G), RS1000377095 (12:112456626 A>T), RS1000389495 (12:112464897 A>G)

Disease associations

OMIM: gene MIM:176876 | disease phenotypes: MIM:156250, MIM:163950, MIM:607785, MIM:151100, MIM:612219, MIM:609942, MIM:613563, MIM:607411, MIM:236750, MIM:277700, MIM:115150, MIM:601321, MIM:126800, MIM:169300, MIM:268210, MIM:192500, MIM:607086, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome 1	Definitive	Autosomal dominant
Noonan syndrome with multiple lentigines	Definitive	Autosomal dominant
Noonan syndrome	Definitive	Autosomal dominant
LEOPARD syndrome 1	Definitive	Autosomal dominant
metachondromatosis	Strong	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant
cardiofaciocutaneous syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Noonan syndrome	Definitive	AD
Costello syndrome	Disputed	AD
cardiofaciocutaneous syndrome	Disputed	AD
Noonan syndrome with multiple lentigines	Definitive	AD

Mondo (50): RASopathy (MONDO:0021060), metachondromatosis (MONDO:0007979), Noonan syndrome 1 (MONDO:0008104), juvenile myelomonocytic leukemia (MONDO:0011908), LEOPARD syndrome 1 (MONDO:0100082), Ewing sarcoma (MONDO:0012817), Noonan syndrome (MONDO:0018997), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), thrombocytopenia (MONDO:0002049), hereditary neoplastic syndrome (MONDO:0015356), Noonan syndrome 3 (MONDO:0012371), Noonan syndrome with multiple lentigines (MONDO:0007893), CBL-related disorder (MONDO:0013308), tricuspid valve insufficiency (MONDO:0002870), patent ductus arteriosus (MONDO:0011827)

Orphanet (38): RASopathy (Orphanet:536391), Metachondromatosis (Orphanet:2499), Noonan syndrome with multiple lentigines (Orphanet:500), Noonan syndrome (Orphanet:648), Juvenile myelomonocytic leukemia (Orphanet:86834), OBSOLETE: Neuroepithelioma (Orphanet:2677), Skeletal Ewing sarcoma (Orphanet:319), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Inherited cancer-predisposing syndrome (Orphanet:140162), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Noonan syndrome-like disorder with juvenile myelomonocytic leukemia (Orphanet:363972), Atrial septal defect, ostium secundum type (Orphanet:99103), Non-immune hydrops fetalis (Orphanet:363999), Rare hypertrophic cardiomyopathy (Orphanet:217569), Lymphoma (Orphanet:223735)

HPO phenotypes

161 total (30 of 161 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000078	Abnormality of the genital system
HP:0000122	Unilateral renal agenesis
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000242	Parietal bossing
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000271	Abnormality of the face
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST000043_1	Type 1 diabetes	2.000000e-14
GCST000498_12	Hematological parameters	8.000000e-12
GCST000847_3	Retinal vascular caliber	2.000000e-13
GCST001072_7	Blood pressure	8.000000e-31
GCST001074_7	Blood pressure	1.000000e-35
GCST001337_38	Platelet count	1.000000e-08
GCST001474_12	Hypothyroidism	3.000000e-12
GCST001791_45	Urate levels	7.000000e-12
GCST001807_5	Tetralogy of Fallot	8.000000e-11
GCST002318_56	Rheumatoid arthritis	7.000000e-09
GCST003272_10	Systolic blood pressure	7.000000e-09
GCST003273_11	Diastolic blood pressure	2.000000e-11
GCST005439_1	Response to alcohol consumption (flushing response)	2.000000e-14
GCST005440_17	Alcohol dependence symptom count	6.000000e-10
GCST005441_8	Alcohol consumption (max-drinks)	2.000000e-12
GCST005951_1	Body mass index	4.000000e-12
GCST006190_39	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-20
GCST006190_55	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-14
GCST006192_12	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	6.000000e-19
GCST006192_26	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-12
GCST006193_22	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-17
GCST006193_63	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-11
GCST006195_4	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-10
GCST006195_52	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-16
GCST006231_58	Mean arterial pressure	8.000000e-16
GCST006268_246	Reaction time	5.000000e-08
GCST006268_473	Reaction time	2.000000e-09
GCST006959_106	Rheumatoid arthritis	8.000000e-08
GCST006959_69	Rheumatoid arthritis	2.000000e-07
GCST007267_133	Systolic blood pressure	1.000000e-11

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004731	eye measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004531	urate measurement
EFO:0007835	alcohol dependence measurement
EFO:0004340	body mass index
EFO:0006527	smoking status measurement
EFO:0006340	mean arterial pressure
EFO:0008393	reaction time measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009929	Beta blocking agent use measurement
EFO:0009928	Diuretic use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (34)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D001763	Blepharoptosis	C11.338.204
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D004370	Duane Retraction Syndrome	C10.292.562.700.375.500; C11.270.235; C11.590.436.400.500; C16.320.290.235
D004374	Ductus Arteriosus, Patent	C14.240.400.340; C14.280.400.340; C16.131.240.400.340
D005660	Funnel Chest	C05.116.099.386; C05.660.386; C16.131.621.386
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525
D008223	Lymphoma	C04.557.386; C15.604.515.569; C20.683.515.761
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D065886	Neurodevelopmental Disorders	F03.625
D009455	Neurofibroma	C04.557.580.600.580; C10.551.775.500.750; C10.668.829.725.500.600
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D012512	Sarcoma, Ewing	C04.557.450.565.575.650.800; C04.557.450.795.620.800
D012600	Scoliosis	C05.116.900.800.875
D000067559	Specific Learning Disorder	C10.597.606.150.550.700; C23.888.592.604.150.550.700; F03.625.374.188.700; F03.625.562.700
D013285	Strabismus	C10.292.562.887; C11.590.810
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
D014262	Tricuspid Valve Insufficiency	C14.280.484.856
D014652	Vascular Diseases	C14.907
D014898	Werner Syndrome	C16.320.925; C18.452.284.960
C566906	Cakut (supp.)
C535579	Cardiofaciocutaneous syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3864 (SINGLE PROTEIN), CHEMBL4630742 (PROTEIN-PROTEIN INTERACTION), CHEMBL4879528 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 33,974 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1756	ESTRAMUSTINE PHOSPHATE	4	56
CHEMBL230006	ENOXOLONE	2	24,361
CHEMBL3351077	CEFSULODIN	2	6,949
CHEMBL4650521	BATOPROTAFIB	2	1,533
CHEMBL5314427	VOCIPROTAFIB	2	69
CHEMBL5095185	JAB-3068	1	947
CHEMBL5543051	PF-07284892	1	34
CHEMBL5761940	BBP-398	1	25

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Protein tyrosine phosphatases non-receptor type (PTPN)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
batoprotafib	Inhibition	7.96	pIC50
migoprotafib	Inhibition	6.77	pIC50

Binding affinities (BindingDB)

1041 measured of 1185 human assays (1193 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1S)-1’-[7-amino-8-[[2-(trifluoromethyl)-3-pyridinyl]sulfanyl]imidazo[1,2-c]pyrimidin-5-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	0.8 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
(1S)-1’-[8-[[3-chloro-2-(cyclopropylamino)-4-pyridinyl]sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	1 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
(5S)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	1.3 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(7-chloro-1,3-benzothiazol-6-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	1.5 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
(3R)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]spiro[3H-1-benzofuran-2,4’-piperidine]-3-amine	IC50	1.8 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
(1S)-1’-[7-amino-8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]imidazo[1,2-c]pyrimidin-5-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	1.9 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
1-[3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-N,4-dimethylpiperidin-4-amine	IC50	2 nM	US-10280171: Heterocyclic inhibitors of PTPN11
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(3,4-dichloro-2-methylindazol-5-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	2 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-[3,4-dichloro-2-(fluoromethyl)indazol-5-yl]-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	2 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
2-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-5-(3,4-dichloro-2-methylindazol-5-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	2 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
(1S)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]-6-methoxyspiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	2.1 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(7-chloro-2-methyl-1,3-benzothiazol-6-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	2.5 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
2-[(1R,2R,4S)-2-amino-2-methyl-7-azabicyclo[2.2.1]heptan-7-yl]-5-(3,4-dichloro-2-methylindazol-5-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	2.5 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(3-chloro-4-fluoro-2-methylindazol-5-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	2.8 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
(1S)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-(fluoromethyl)imidazo[1,2-c]pyrimidin-5-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	2.9 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
(2S,4R)-4-amino-8-[6-amino-5-[(2,3-dichloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]-8-azaspiro[4.5]decan-2-ol	IC50	3 nM	US-10336774: N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	3 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
(5S)-1’-[7-(5-chlorothiophen-2-yl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	3 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(5S)-1’-[7-(3,4-difluorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	3 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(6S)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]spiro[4,6-dihydrocyclopenta[d][1,3]thiazole-5,4’-piperidine]-6-amine	IC50	3.1 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(4-chloro-2-ethylindazol-5-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	3.3 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(5-chloro-3-methoxyquinoxalin-6-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	3.3 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
3-[5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyrazin-2-yl]sulfanyl-2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-ol	IC50	3.5 nM	US-11459340: Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
6-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-3-(3,4-dichloro-2-ethylindazol-5-yl)-5-methyl-3aH-pyrazolo[3,4-d]pyrimidin-4-one	IC50	3.7 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
(1S)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]-5-fluoro-6-methylspiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	3.7 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	3.8 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
(2R,4R)-4-amino-8-[6-amino-5-[(2,3-dichloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]-8-azaspiro[4.5]decan-2-ol	IC50	4 nM	US-10336774: N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
(2R,4R)-8-[6-amino-5-[(2,3-dichloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]-2-methoxy-8-azaspiro[4.5]decan-4-amine	IC50	4 nM	US-10336774: N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
(3S,4S)-8-[6-amino-5-[(6-amino-2,3-dichloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine	IC50	4 nM	US-10336774: N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
(2S,4R)-4-amino-8-[6-amino-5-[(6-amino-2,3-dichloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]-8-azaspiro[4.5]decan-2-ol	IC50	4 nM	US-10336774: N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
(5S)-1’-[7-(2-chlorothiophen-3-yl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(5S)-1’-[7-(5-chloroquinoxalin-6-yl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(6S)-1’-[7-(5-chloroquinoxalin-6-yl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-2-methylspiro[4,6-dihydrocyclopenta[d][1,3]thiazole-5,4’-piperidine]-6-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(1S)-1’-[7-(3-fluoro-2-methyl-4-pyridinyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-6-methoxyspiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(1S)-1’-[7-(3-chloro-4-pyridinyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-6-methoxyspiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(1S)-1’-[7-(5-chloro-1-methylpyrazol-4-yl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-6-methoxyspiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(7S)-1’-[7-(2-fluorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[c]pyridine-6,4’-piperidine]-7-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(7S)-1’-(6-methyl-7-phenylpyrazolo[1,5-a]pyrazin-4-yl)spiro[5,7-dihydrocyclopenta[c]pyridine-6,4’-piperidine]-7-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(7S)-1’-[7-(3-chloro-2-methyl-4-pyridinyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[c]pyridine-6,4’-piperidine]-7-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(3R)-1’-[7-(3-chloro-2-methyl-4-pyridinyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[1,3-dihydroindole-2,4’-piperidine]-3-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(5S)-1’-[7-(2,3-dihydro-1-benzofuran-6-yl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(5S)-1’-[7-(2,3-difluoro-4-methoxyphenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
2-[4-[4-[(5S)-5-aminospiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-1’-yl]-6-methylpyrazolo[1,5-a]pyrazin-7-yl]phenyl]acetonitrile	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(5S)-1’-[7-(2,5-difluorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(5S)-1’-[7-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-pyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	IC50	4 nM	US-20250282782: PYRAZOLOPYRAZINE COMPOUNDS AS SHP2 INHIBITORS
(1S)-1’-[8-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-7-methylimidazo[1,2-c]pyrimidin-5-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	IC50	4.4 nM	US-12281118: Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method, and use
2-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-5-(4-chloro-2-methylindazol-5-yl)-3-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one	IC50	4.5 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
6-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-3-(7-chloro-2-methyl-1,3-benzothiazol-6-yl)-5-methyl-3aH-pyrazolo[3,4-d]pyrimidin-4-one	IC50	4.5 nM	US-12037345: Heterobicyclic compounds for inhibiting the activity of SHP2
3-[5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyrazin-2-yl]sulfanyl-2-chloro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-6-ol	IC50	4.8 nM	US-11459340: Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
(4R)-8-[6-amino-5-[(3-chloro-2-fluoro-4-pyridinyl)sulfanyl]pyrazin-2-yl]-8-azaspiro[4.5]decan-4-amine	IC50	5 nM	US-10336774: N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2

ChEMBL bioactivities

3098 potent at pChembl≥5 of 3478 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.77	IC50	0.017	nM	CHEMBL4858291
10.23	IC50	0.0583	nM	CHEMBL4752026
9.89	IC50	0.13	nM	CHEMBL5618343
9.89	IC50	0.13	nM	CHEMBL5618733
9.84	IC50	0.145	nM	CHEMBL4060033
9.77	IC50	0.17	nM	CHEMBL5619476
9.70	IC50	0.202	nM	CHEMBL4871539
9.52	IC50	0.3	nM	CHEMBL5784512
9.43	Kd	0.37	nM	CHEMBL5595838
9.40	IC50	0.4	nM	CHEMBL5183738
9.38	Kd	0.42	nM	CHEMBL5591410
9.30	IC50	0.5	nM	CHEMBL5784512
9.28	Kd	0.53	nM	CHEMBL4752051
9.23	IC50	0.583	nM	CHEMBL5287751
9.23	IC50	0.583	nM	CHEMBL4752026
9.23	IC50	0.59	nM	CHEMBL5619863
9.22	Kd	0.6	nM	CHEMBL5276842
9.22	IC50	0.6	nM	CHEMBL5619365
9.22	IC50	0.6	nM	CHEMBL5838528
9.15	IC50	0.7	nM	CHEMBL4794480
9.10	IC50	0.8	nM	CHEMBL4757590
9.10	IC50	0.8	nM	CHEMBL5897159
9.05	IC50	0.9	nM	CHEMBL5792033
9.04	Kd	0.92	nM	CHEMBL4752599
9.00	IC50	1	nM	CHEMBL4752245
9.00	IC50	1	nM	CHEMBL4797428
9.00	IC50	1	nM	CHEMBL4794480
9.00	IC50	1	nM	CHEMBL5183738
9.00	IC50	1	nM	CHEMBL5412259
9.00	IC50	1	nM	CHEMBL5874591
9.00	IC50	1	nM	CHEMBL6065803
9.00	IC50	1	nM	CHEMBL6064396
9.00	IC50	1	nM	CHEMBL5882319
9.00	IC50	1	nM	CHEMBL5924671
9.00	IC50	1	nM	CHEMBL5871235
8.99	IC50	1.03	nM	CHEMBL5619074
8.97	IC50	1.08	nM	CHEMBL5619866
8.96	IC50	1.1	nM	CHEMBL5784512
8.92	Kd	1.2	nM	CHEMBL5591213
8.92	Kd	1.2	nM	CHEMBL5583655
8.92	IC50	1.2	nM	CHEMBL5862243
8.89	IC50	1.29	nM	VOCIPROTAFIB
8.89	Kd	1.3	nM	CHEMBL4789817
8.89	IC50	1.29	nM	CHEMBL5992507
8.85	IC50	1.4	nM	CHEMBL4750774
8.85	IC50	1.4	nM	CHEMBL5784512
8.82	IC50	1.5	nM	CHEMBL4752026
8.82	IC50	1.5	nM	VOCIPROTAFIB
8.82	IC50	1.5	nM	CHEMBL6009513
8.81	IC50	1.55	nM	CHEMBL4752026

PubChem BioAssay actives

972 with measured affinity, of 2580 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3S,4S)-8-[6-amino-5-(3-amino-2-chlorophenyl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine	1764591: Inhibition of human SHP2 catalytic activity in human MV4-11 cells	ic50	<0.0001	uM
6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine	1764591: Inhibition of human SHP2 catalytic activity in human MV4-11 cells	ic50	0.0001	uM
[3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol	1937999: Inhibition of wildtype SHP2 (unknown origin)	ic50	0.0001	uM
N-[3-[5-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-4-oxo-1H-pyridine-3-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0001	uM
N-[3-[5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-2-oxo-1H-pyridine-3-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0001	uM
N’-[3-[3-amino-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-N-[3-[2-[2-[3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]propoxy]ethoxy]ethoxy]propyl]butanediamide	1764591: Inhibition of human SHP2 catalytic activity in human MV4-11 cells	ic50	0.0002	uM
N-[3-[5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-4-oxo-1H-pyridine-3-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0002	uM
(4S)-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[4,6-dihydrocyclopenta[b]thiophene-5,4’-piperidine]-4-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0004	uM
(5S)-1’-[5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0004	uM
[6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2H-pyrazolo[3,4-b]pyrazin-5-yl]methanol	1847584: Inhibition of human SHP2 assessed as downregulation of PERK level in human KYSE520 cells incubated for 2 hrs by Alpha screen assay	ic50	0.0004	uM
(5S)-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0005	uM
(1S)-1’-[5-[[2-(trifluoromethyl)-3-pyridinyl]sulfanyl]-3H-imidazo[4,5-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	1923292: Binding affinity to N-terminal biotinylated AviTag-G4SG4S-tagged recombinant SHP2 (1 to 525 residues) (unknown origin) by SPR analysis	kd	0.0006	uM
[3-[(3S,4R)-4-amino-3-methyl-1-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol	1921216: Inhibition of full length SHP2 (unknown origin) using DiFMUP as substrate preincubated for 30 mins followed by substrate addition	ic50	0.0006	uM
N-[3-[5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-3-hydroxypyridine-2-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0006	uM
N-[3-[5-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-3-hydroxypyridine-2-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0006	uM
6-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4-one	1684819: Antagonist activity at recombinant human N-terminal His6-tagged full length SHP2 expressed in Escherichia coli using DiFMUP as substrate measured after 60 mins in presence of IRS1-2pY peptide by fluorescence assay	ic50	0.0008	uM
(5S)-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[c]pyridine-6,4’-piperidine]-5-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0009	uM
N-[3-[3-amino-5-[(4R)-4-amino-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-2-hydroxy-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxamide	1674063: Allosteric inhibition of [IRSl_pY1172(dPEG8)pY1222] peptide-activated SHP2 (unknown origin) using DiFMUP as substrate preincubated for 30 to 60 mins followed by substrate addition and measured after 30 mins by fluorescence method	ic50	0.0010	uM
6-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4-one	1684819: Antagonist activity at recombinant human N-terminal His6-tagged full length SHP2 expressed in Escherichia coli using DiFMUP as substrate measured after 60 mins in presence of IRS1-2pY peptide by fluorescence assay	ic50	0.0010	uM
6-[(5R)-5-aminospiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-1’-yl]-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4-one	1684819: Antagonist activity at recombinant human N-terminal His6-tagged full length SHP2 expressed in Escherichia coli using DiFMUP as substrate measured after 60 mins in presence of IRS1-2pY peptide by fluorescence assay	ic50	0.0010	uM
(1S)-1’-[3-(3,4-dihydro-2H-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	2016431: Inhibition of wild-type full-length SHP2 (unknown origin) expressed in Escherichia coli BL21(DE3) using DiFMUP as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0010	uM
(5S)-5-amino-1’-[7-(2,3-difluorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydro-1H-cyclopenta[b]pyridine-6,4’-piperidine]-2-one	2016784: Inhibition of full length N-terminal his6-tagged human recombinant SHP2 phosphatase activity using DiFMUP as substrate incubated for 30 mins	ic50	0.0010	uM
(3R)-1’-[3-(3,4-dihydro-2H-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]spiro[3H-1-benzofuran-2,4’-piperidine]-3-amine;hydrochloride	2016431: Inhibition of wild-type full-length SHP2 (unknown origin) expressed in Escherichia coli BL21(DE3) using DiFMUP as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0010	uM
N-[3-[5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-3-chloropyridine-2-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0010	uM
N-[3-[5-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-3-chloropyridine-2-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0011	uM
(5S)-1’-[6-amino-5-[(3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0012	uM
(5S)-1’-[6-amino-5-[[3-chloro-2-(methylamino)-4-pyridinyl]sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0012	uM
[6-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl]methanol	2087219: Inhibition of wild type SHP2 (unknown origin)	ic50	0.0013	uM
(1S)-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0013	uM
6-[(3R)-3-aminospiro[3H-1-benzofuran-2,4’-piperidine]-1’-yl]-3-(2,3-dichlorophenyl)-2,5-dimethylpyrimidin-4-one	1684819: Antagonist activity at recombinant human N-terminal His6-tagged full length SHP2 expressed in Escherichia coli using DiFMUP as substrate measured after 60 mins in presence of IRS1-2pY peptide by fluorescence assay	ic50	0.0014	uM
(3S)-3-amino-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-5-carbonitrile	2114328: Inhibition of LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQKASINFQK-NH2-activated SHP2 (unknown origin) using DiFMUP as substrate pretreated with enzyme for 30 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0016	uM
(4S)-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[4,6-dihydrocyclopenta[d][1,3]thiazole-5,4’-piperidine]-4-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0016	uM
(5S)-1’-[6-amino-5-[[3-chloro-2-(dimethylamino)-4-pyridinyl]sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0016	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-oxobutanoic acid	1807826: Binding affinity to human His-tagged SHP2 N-SH2 domain (2 to 111 residues) expressed in Escherichia coli (DE3) Rosetta2 competent cells assessed as dissociation constant by fluorescence anisotropy assay	kd	0.0016	uM
N-[3-[5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl]sulfanyl-2-chlorophenyl]-3-chloropyridine-2-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0017	uM
N-[3-[5-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]pyrazin-2-yl]sulfanyl-2-chlorophenyl]-2-oxo-1H-pyridine-3-carboxamide	2131058: Allosteric inhibition of N-terminal His-tagged human recombinant SHP2 extracted from Escherichia coli using DiFMUP as substrate preincubated with compound for 60 mins followed by substrate addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0019	uM
(7S)-1’-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-7-amine	2114329: Binding affinity to SHP2 (unknown origin) by SPR analysis	kd	0.0020	uM
6-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]-3-(2-chloro-4-fluoro-3-methylphenyl)-2,5-dimethylpyrimidin-4-one	1684819: Antagonist activity at recombinant human N-terminal His6-tagged full length SHP2 expressed in Escherichia coli using DiFMUP as substrate measured after 60 mins in presence of IRS1-2pY peptide by fluorescence assay	ic50	0.0020	uM
6-[(1S)-1-aminospiro[1,3-dihydroindene-2,4’-piperidine]-1’-yl]-3-(2,3-dichloro-4-fluorophenyl)-2,5-dimethylpyrimidin-4-one	1684819: Antagonist activity at recombinant human N-terminal His6-tagged full length SHP2 expressed in Escherichia coli using DiFMUP as substrate measured after 60 mins in presence of IRS1-2pY peptide by fluorescence assay	ic50	0.0020	uM
[(1S,6R,7S)-3-[3-(7-chloro-2-methyl-1,3-benzothiazol-6-yl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-7-(4-methyl-1,3-thiazol-2-yl)-3-azabicyclo[4.1.0]heptan-7-yl]methanamine	1956327: Allosteric inhibition of recombinant human SHP2 using IRS1 peptide and DiFMUP as substrate incubated for 30 mins followed by DiFMUP addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0020	uM
[6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-[3-chloro-2-(propylamino)-4-pyridinyl]-2H-pyrazolo[3,4-b]pyrazin-5-yl]methanol	1847584: Inhibition of human SHP2 assessed as downregulation of PERK level in human KYSE520 cells incubated for 2 hrs by Alpha screen assay	ic50	0.0020	uM
(5S)-1’-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2016784: Inhibition of full length N-terminal his6-tagged human recombinant SHP2 phosphatase activity using DiFMUP as substrate incubated for 30 mins	ic50	0.0020	uM
(5S)-1’-[7-(2-fluoro-4-methylphenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4’-piperidine]-5-amine	2016784: Inhibition of full length N-terminal his6-tagged human recombinant SHP2 phosphatase activity using DiFMUP as substrate incubated for 30 mins	ic50	0.0020	uM
(4S)-8-[3-(2,3-dichlorophenyl)sulfanyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine	1845964: Inhibition of N-terminal 6His-tagged full-length H2N-VE(pY)LDLDLD(PEG8)RVD(pY)VVVDQQ-amide-activated SHP2 (247 to 529 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) using DiFMUP as substrate preincubated for 10 to 30 mins with activating peptide prior to compound addition for 30 mins followed by substrate addition and measured for 6 mins by fluorescence based assay	ic50	0.0021	uM
4-[[6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]sulfanyl]-3-chloropyridin-2-amine	2016431: Inhibition of wild-type full-length SHP2 (unknown origin) expressed in Escherichia coli BL21(DE3) using DiFMUP as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0030	uM
6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-[2,3-dichloro-4-(1-methylpyrazol-3-yl)oxyphenyl]-2,5-dimethylpyrimidin-4-one	1674050: Inhibition of human SHP2 E76K mutant expressed in Escherichia coli using DiFMUP as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorescence method	ic50	0.0030	uM
[6-[(1R,2S,3S,5S)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octan-8-yl]-3-(7-chloro-1,3-benzothiazol-6-yl)-2H-pyrazolo[3,4-b]pyrazin-5-yl]methanol	1674052: Allosteric inhibition of SHP2 (unknown origin) using DiFMUP as substrate preincubated for 30 mins in presence of activating peptide [IRSl_pY1172(dPEG8)pY1222] followed by substrate addition and measured over 30 mins by fluorescence method	ic50	0.0030	uM
(1S)-1’-[5-[(3-chloro-4-pyridinyl)sulfanyl]-3H-imidazo[4,5-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4’-piperidine]-1-amine	1923289: Allosteric inhibition of IRS1 peptide-activated human recombinant SHP2 (Met1 to Leu525) expressed in Escherichia coli assessed as inhibition of dephosphorylation of 6,8-difluoro-4-methylumbelliferyl phosphate using DiFMUP as substrate preincubated with enzyme for 30 mins followed by substrate addition and measured after 30 mins by DiFMUP assay	ic50	0.0030	uM
(2R)-1’-[3-(3,4-dihydro-2H-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]spiro[1,2-dihydroindene-3,4’-piperidine]-2-amine	2016431: Inhibition of wild-type full-length SHP2 (unknown origin) expressed in Escherichia coli BL21(DE3) using DiFMUP as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0030	uM
[(1S,6R,7S)-3-[3-(4-chloropyrazolo[1,5-a]pyridin-5-yl)-2H-pyrazolo[3,4-b]pyrazin-6-yl]-7-(4-methyl-1,3-thiazol-2-yl)-3-azabicyclo[4.1.0]heptan-7-yl]methanamine	1956327: Allosteric inhibition of recombinant human SHP2 using IRS1 peptide and DiFMUP as substrate incubated for 30 mins followed by DiFMUP addition and measured after 30 mins by fluorescence based microplate reader analysis	ic50	0.0030	uM

CTD chemical–gene interactions

85 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	3
sodium arsenite	affects cotreatment, decreases expression	3
NSC-87877	increases phosphorylation, affects cotreatment, decreases activity, decreases phosphorylation, decreases reaction (+1 more)	3
Resveratrol	affects binding, decreases reaction, increases reaction, decreases activity, increases oxidation (+2 more)	3
Tretinoin	affects cotreatment, decreases expression	3
cobaltous chloride	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Cadmium Chloride	increases abundance, increases palmitoylation, decreases expression, decreases reaction	2
SHP099	decreases activity	1
geranylnaringenin	affects binding, increases phosphorylation, affects reaction, decreases phosphorylation	1
dihydrotanshinone I	decreases expression, affects reaction, decreases reaction, increases phosphorylation	1
tubocapsenolide A	increases activity, affects cotreatment, decreases activity, decreases reaction, affects reaction (+2 more)	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
capillarisin	increases expression, affects reaction, decreases phosphorylation, increases cleavage	1
tributyltin	increases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	decreases activity	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
perfluorooctanoic acid	increases expression, affects binding, decreases activity	1
ochratoxin A	increases expression	1
benzo(e)pyrene	decreases methylation	1
methylmercury II	increases expression	1
anthranilic acid	affects binding, decreases activity	1
perfluorobutyric acid	affects binding, decreases activity	1
perfluorodecanoic acid	affects binding, decreases activity	1

ChEMBL screening assays

588 unique, capped per target: 585 binding, 2 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1063852	Binding	Inhibition of GST-tagged human SHP2	Synthesis and biological evaluation of heterocyclic ring-substituted maslinic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B. — Bioorg Med Chem Lett
CHEMBL1963930	Functional	PUBCHEM_BIOASSAY: Dose Response selectivity of inhibitors of Striatal-Enriched Phosphatase (STEP) in a SHP2 (PTPN11) Inhibition Assay. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL4626294	ADMET	Inhibition of SHP2 (unknown origin) expressed in Escherichia coli BL21 using p-nitrophenyl phosphate as substrate measured after 30 mins by UV-vis spectrophotometric method	Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B. — J Med Chem

Cellosaurus cell lines

79 cell lines: 63 cancer cell line, 15 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0007	U-937	Cancer cell line	Male
CVCL_0C65	INV-3	Cancer cell line	Sex unspecified
CVCL_1478	NCI-H1573	Cancer cell line	Female
CVCL_1775	TUR	Cancer cell line	Male
CVCL_1927	YNH-1	Cancer cell line	Male
CVCL_2082	JOSK-I	Cancer cell line	Male
CVCL_2083	JOSK-M	Cancer cell line	Male
CVCL_2810	U-937 cl1-14	Cancer cell line	Male
CVCL_2811	U-937 cl1-22	Cancer cell line	Male
CVCL_2Z95	U937-DC-SIGN	Cancer cell line	Male

Clinical trials (associated diseases)

318 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01339988	PHASE4	UNKNOWN	Busulfan and Cyclophosphamide Instead of Total Boby Irradiation (TBI) and Cyclophosphamide for Hematological Malignancies Hematocrit (HCT)
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00002798	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
NCT00152139	PHASE3	COMPLETED	Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00186823	PHASE3	COMPLETED	Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00450450	PHASE3	COMPLETED	Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases
NCT00799461	PHASE3	COMPLETED	Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications
NCT00843882	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
NCT01241500	PHASE3	COMPLETED	Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT01749111	PHASE3	TERMINATED	Comparison Between Cyclophosphamide and Combination of Methotrexate + Calcineurin Inhibitor for GVHD Prophylaxis
NCT01928537	PHASE3	COMPLETED	Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine
NCT03306264	PHASE3	COMPLETED	Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML
NCT04842604	PHASE3	COMPLETED	Continuation Study of B1371019(NCT03416179) and B1371012(NCT02367456) Evaluating Azacitidine With Or Without Glasdegib In Patients With Previously Untreated AML, MDS or CMML
NCT05515029	PHASE3	ACTIVE_NOT_RECRUITING	Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis
NCT06647862	PHASE3	RECRUITING	IMM01+Azacitidine VS Placebo +Azacitidine in Patients With Newly Diagnosed Chronic Myelomonocytic Leukemia (CMML1-2)
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00015990	PHASE2	COMPLETED	Thalidomide in Treating Patients With Myelodysplastic Syndrome
NCT00025038	PHASE2	COMPLETED	Combination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplant in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia
NCT00039416	PHASE2	COMPLETED	Imatinib Mesylate in Treating Patients With Myelofibrosis
NCT00067808	PHASE2	COMPLETED	Study of Three Different Schedules of Low-Dose Decitabine in Myelodysplastic Syndrome (MDS)
NCT00079313	PHASE2	COMPLETED	Imatinib (Gleevec(Registered Trademark)) to Treat Chronic Myelomonocytic Leukemia and Atypical Chronic Myelogenous Leukemia
NCT00084916	PHASE2	COMPLETED	CCI-779 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, or Chronic Myelogenous Leukemia in Blastic Phase
NCT00113321	PHASE2	TERMINATED	Low-Dose Decitabine in Myelodysplastic Syndrome Post Azacytidine Failure
NCT00118352	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
NCT00119366	PHASE2	TERMINATED	Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
NCT00136409	PHASE2	COMPLETED	A Study of Gleevec in Patients With Idiopathic Myelofibrosis or Chronic Myelomonocytic Leukemia (CMML)
NCT00143559	PHASE2	COMPLETED	Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies
NCT00145613	PHASE2	COMPLETED	Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies
NCT00171912	PHASE2	COMPLETED	Imatinib Mesylate in Patients With Various Types of Malignancies Involving Activated Tyrosine Kinase Enzymes
NCT00299156	PHASE2	COMPLETED	Oral Clofarabine Study in Patients With Myelodysplastic Syndrome
NCT00309907	PHASE2	COMPLETED	Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant
NCT00313586	PHASE2	COMPLETED	Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia