INPPL1

Summary

INPPL1 (inositol polyphosphate phosphatase like 1, HGNC:6080) is a protein-coding gene on chromosome 11q13.4, encoding Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (O15357). Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways.

The protein encoded by this gene is an SH2-containing 5’-inositol phosphatase that is involved in the regulation of insulin function. The encoded protein also plays a role in the regulation of epidermal growth factor receptor turnover and actin remodelling. Additionally, this gene supports metastatic growth in breast cancer and is a valuable biomarker for breast cancer.

Source: NCBI Gene 3636 — RefSeq curated summary.

At a glance

• Gene–disease (curated): opsismodysplasia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 757 total — 26 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 86
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6080
Approved symbol	INPPL1
Name	inositol polyphosphate phosphatase like 1
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	SHIP2
Ensembl gene	ENSG00000165458
Ensembl biotype	protein_coding
OMIM	600829
Entrez	3636

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 22 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000298229, ENST00000320683, ENST00000535985, ENST00000537656, ENST00000537755, ENST00000538339, ENST00000538751, ENST00000540329, ENST00000540973, ENST00000541303, ENST00000541544, ENST00000541752, ENST00000543234, ENST00000544806, ENST00000545355, ENST00000924950, ENST00000924951, ENST00000924952, ENST00000924953, ENST00000924954, ENST00000924955, ENST00000924956, ENST00000924957, ENST00000924958, ENST00000924959, ENST00000924960, ENST00000946902, ENST00000946903, ENST00000946904

RefSeq mRNA: 1 — MANE Select: NM_001567 NM_001567

CCDS: CCDS8213

Canonical transcript exons

ENST00000298229 — 28 exons

Exon	Start	End
ENSE00001093211	72230121	72230271
ENSE00001093213	72230993	72231189
ENSE00001093215	72237124	72237796
ENSE00001093228	72229924	72230019
ENSE00001093242	72232626	72232764
ENSE00001093249	72235846	72235986
ENSE00001093251	72232240	72232336
ENSE00001093253	72229663	72229752
ENSE00002497360	72230796	72230898
ENSE00003461850	72224767	72225166
ENSE00003469466	72234527	72234615
ENSE00003472448	72233655	72233744
ENSE00003482200	72233075	72233163
ENSE00003484446	72229090	72229230
ENSE00003484968	72235296	72235451
ENSE00003520335	72228348	72228498
ENSE00003559440	72232875	72232974
ENSE00003562475	72229465	72229558
ENSE00003593444	72228190	72228253
ENSE00003618061	72234281	72234394
ENSE00003618255	72231498	72231615
ENSE00003634116	72235675	72235753
ENSE00003643188	72235116	72235203
ENSE00003691314	72233441	72233522
ENSE00003692410	72228727	72228847
ENSE00003743842	72238042	72238175
ENSE00003786971	72230362	72230468
ENSE00003845054	72238263	72239147

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 98.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.5416 / max 145.9400, expressed in 1818 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115737	15.3828	1811
115741	3.7753	1519
115738	1.4558	936
115743	0.4180	206
206371	0.2443	93
115736	0.2387	108
115742	0.0267	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	98.78	gold quality
stromal cell of endometrium	CL:0002255	98.72	gold quality
right lobe of thyroid gland	UBERON:0001119	98.43	gold quality
metanephros cortex	UBERON:0010533	98.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.34	gold quality
left lobe of thyroid gland	UBERON:0001120	98.29	gold quality
right uterine tube	UBERON:0001302	98.23	gold quality
right ovary	UBERON:0002118	98.20	gold quality
granulocyte	CL:0000094	98.16	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.14	gold quality
lower esophagus	UBERON:0013473	98.13	gold quality
left uterine tube	UBERON:0001303	98.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.05	gold quality
apex of heart	UBERON:0002098	98.03	gold quality
endocervix	UBERON:0000458	97.91	gold quality
body of uterus	UBERON:0009853	97.88	gold quality
left ovary	UBERON:0002119	97.85	gold quality
adenohypophysis	UBERON:0002196	97.82	gold quality
body of stomach	UBERON:0001161	97.65	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.60	gold quality
right lung	UBERON:0002167	97.55	gold quality
transverse colon	UBERON:0001157	97.52	gold quality
ventricular zone	UBERON:0003053	97.46	gold quality
right adrenal gland cortex	UBERON:0035827	97.45	gold quality
descending thoracic aorta	UBERON:0002345	97.44	gold quality
right adrenal gland	UBERON:0001233	97.38	gold quality
right coronary artery	UBERON:0001625	97.33	gold quality
monocyte	CL:0000576	97.32	gold quality
minor salivary gland	UBERON:0001830	97.32	gold quality
upper lobe of left lung	UBERON:0008952	97.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYOD1, PBX1, PKNOX1, PREB

miRNA regulators (miRDB)

29 targeting INPPL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-6793-3P	97.66	65.78	1084
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-2909	96.36	67.30	562
HSA-MIR-3157-3P	95.86	67.08	454

Literature-anchored findings (GeneRIF, showing 40)

• candidate gene for type 2 diabetes (PMID:12086927)
• overexpression strongly reduces the proliferation rate of K562 erythroleukemia cell line (PMID:12147234)
• SHIP phosphorylation by the immunoreceptor tyrosine-based activation motif (ITAM)-associated Fc gamma RIIa requires Shc phosphorylation, leads to activation of Src kinases, and down-regulates NF-kappa B-induced gene transcription during phagocytosis. (PMID:12370370)
• regulation of FcgammaR-mediated activation of human myeloid cells by the expression and function of the inositol phosphatase SHIP-2 (PMID:12690104)
• INPPL1 variants may impact susceptibility to disease and/or to subphenotypes involved in the metabolic syndrome in some diabetic patients. (PMID:15220217)
• Schizosaccharomyces pombe synaptojanin (SPsynaptojanin) and human SH2 domain-containing inositol-5-phosphatase SHIP2 comparison: substrate specificity and mechanism study (PMID:15316017)
• SHIP1 and SHIP2 interact preferentially with Tec and inactivate it by de-phosphorylation of local PtdIns 3,4,5-P(3) and inhibition of Tec membrane localization (PMID:15492005)
• A novel regulatory role is suggested for SHIP2 in macrophage colony-stimulating factor (M-CSF)-stimulated myeloid cells. (PMID:15557176)
• SHIP2 plays a distinct role in signaling pathways mediated by integrins and growth factor receptors. (PMID:15668240)
• SHIP-2 accumulates transiently at actin-rich regions along the cellular leading edge in HGF-stimulated MDCK cells; overexpression alters HGF-mediated lamellipodium formation (PMID:15735664)
• Findings suggest that SHIP2 gene expression is controlled by the Sp-family of transcription factors. (PMID:15777721)
• Data report the identification of the cytoskeletal protein vinexin as a protein interacting with SHIP2. (PMID:16302969)
• The SNPs in the SHIP2 gene promoter and the 5’-UTR may account partly for the impaired fasting glycemia and may be a marker for the risk of diabetes (PMID:16804414)
• SHIP2 substitutes for PTEN in the acute regulation of PKB in PC3 cells but not other prostate cell lines, where PTEN may share this role with further PIP3-degrading mechanisms. (PMID:16842970)
• SHIP2 tyrosine phosphorylation and Shc association can be regulated by serine/threonine signaling pathways, either indirectly (via PKC), or directly (via T958) (PMID:17219406)
• In a yeast two-hybrid screen for new interaction partners of Arap3, the PI 5’-phosphatase SHIP2 was identified as an interaction partner of Arap3. (PMID:17314030)
• There was no association of INPPL1 polymorphisms & essential hypertension. Any association may be limited to metabolic syndrome patients with hypertension as part of the phenotype (PMID:17557929)
• ignificance of glucose intolerance in prognosis of male hepaatocellular carcinoma (HCC) patients and down-regulation of SHIP2 expression in HCC. (PMID:17671700)
• shift in the balance of lipid signals is the activation of SHIP2 by increased tyrosine phosphorylation, an effect observed in HeLa cells in response to both PTP inhibitors and epidermal growth factor. (PMID:17672824)
• endogenous SHIP2 in MDA-231 breast cancer cells supports in vitro cell proliferation, increases cellular sensitivity to drugs targeting the EGFR and supports cancer development and metastasis (PMID:17893231)
• These data raise the interesting possibility that SHIP2 inhibition exerts proliferative effects in beta-cells and further support the attractiveness of a specific inhibition of SHIP2 for the treatment of type 2 diabetes. (PMID:18061583)
• Thse data provide a molecular link between SHIP2 and ITSN1 which are involved in receptor endocytosis regulation. (PMID:18692052)
• NMR and ITC (isothermal titration calorimetry) studies on the Sam domain of Ship2 revealing its three-dimensional structure and its possible mode of interaction with the Sam domain from the EphA2 receptor (PMID:18991394)
• the corneal epithelial-specific miR-184 can interfere with the ability of miR-205 to suppress SHIP2 levels (PMID:19033458)
• High expression of obesity-linked phosphatase SHIP2 is associated with invasive breast cancer. (PMID:19065064)
• comparison of expression of SHIP-1, SHIP-2, and Syk protein to histamine release from mast cells cultured from the peripheral blood of chronic idiopathic urticaria responder (R), chronic idiopathic urticaria NR, and normal subjects (PMID:19477690)
• SH2 domain of SHIP2, in conjunction with the C-terminus, confers an inhibitory effect to maintain a low basal activity, and signal-induced tyrosine phosphorylations overcome this effect to activate SHIP2 (PMID:19518129)
• This binding mode of Ship 2 protein is identical to the association between Ship2-Sam and the Sam domain from the Ephrin A2 receptor. (PMID:19765305)
• data highlight a novel biological role of the PP2A(T130) holoenzyme in EGF signaling through interaction with EGFR and the phosphatidylinositol (3,4,5)-trisphosphate 5-phosphatase SHIP2. (PMID:19825976)
• Data suggest that a combination of tissue distribution, specificity, and kinetic differences is likely responsible for SHIP1 and SHIP2 in vivo functional differences. (PMID:19839650)
• SHIP2 (SH2 domain-containing inositol phosphatase 2) SH2 domain negatively controls SHIP2 monoubiquitination in response to epidermal growth factor. (PMID:19880507)
• Data show that SHIP2 localizes to the nucleus and periphery, and has been shown to translocate to the cell membrane following EGF treatment. (PMID:19895833)
• A recent study now shows that two additional tyrosines within Tir recruit the inositol phosphatase SHIP2 to generate a PI(3,4)P2-enriched membrane platform that stabilizes pedestal assembly. (PMID:20114020)
• The authors demonstrate that Y483 and Y511 within tandem ITIM-like sequences of Escherichia coli Tir are essential for recruiting human SHIP2, a host inositol phosphatase. (PMID:20114025)
• LL5beta directs the translocation of filamin A and SHIP2 to sites of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulation, and PtdIns(3,4,5)P3 localization is mutually modified by co-recruited SHIP2. (PMID:20236936)
• Treatment of HEKs and HCEKs with antago-205 increased SHIP2 levels and impaired the ability of these cells to seal linear scratch wounds compared with untreated or irrelevant-antago treatments (PMID:20530248)
• The upregulation of SHIP2 in Zucker rat glomeruli prior to the age of onset of proteinuria suggests a possible role for SHIP2 in the development of podocyte injury. (PMID:20654688)
• The function of SHIP2 is different at the plasma membrane where it recognizes PtdIns(3,4,5)P3, and in the nucleus where it may interact with PtdIns(4,5)P2, particularly in speckles. (PMID:21770892)
• Caveolin-1 knockdown by small interfering RNA reduces H2O2-induced SHP-2 phosphorylation in rat primary astrocytes and in CRT-MG human astroglioma cells. (PMID:21918362)
• results support the hypothesis that SHIP2 may play a critical role in the initiation and progression of LSCC and may serve as both a prognostic marker and a potential therapeutic target in patients with LSCC (PMID:22079859)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	inppl1a	ENSDARG00000104222
mus_musculus	Inppl1	ENSMUSG00000032737
rattus_norvegicus	Inppl1	ENSRNOG00000019730
drosophila_melanogaster	Synj	FBGN0034691
caenorhabditis_elegans		WBGENE00006763

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), SYNJ1 (ENSG00000159082), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), INPP5B (ENSG00000204084), SACM1L (ENSG00000211456)

Protein

Protein identifiers

Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 — O15357 (reviewed: O15357)

Alternative names: Inositol polyphosphate phosphatase-like protein 1, Protein 51C, SH2 domain-containing inositol 5’-phosphatase 2

All UniProt accessions (8): O15357, F5GWY9, F5GY16, F5GYK9, F5H588, H0YFB4, H0YFZ4, H7BXR2

UniProt curated annotations — full annotation on UniProt →

Function. Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Required for correct mitotic spindle orientation and therefore progression of mitosis. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. Plays a role in the localization of AURKA and NEDD9/HEF1 to the basolateral membrane at interphase in polarized cysts, thereby mediates cell cycle homeostasis, cell polarization and cilia assembly. Additionally promotion of cilia growth is also facilitated by hydrolysis of (PtdIns(3,4,5)P3) to PtdIns(3,4)P2. Promotes formation of apical membrane-initiation sites during the initial stages of lumen formation via Rho family-induced actin filament organization and CTNNB1 localization to cell-cell contacts. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification.

Subunit / interactions. Interacts with tyrosine phosphorylated form of SHC1. Interacts with EGFR. Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR. Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells. Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin. Interacts with c-Met/MET, when c-Met/MET is phosphorylated on ‘Tyr-1356’. Interacts with p130Cas/BCAR1. Interacts with CENTD3/ARAP3 via its SAM domain. Interacts with c-Cbl/CBL and CAP/SORBS1. Interacts with activated EPHA2 receptor. Interacts with receptor FCGR2A. Interacts with receptor FCGR2B. Interacts with tyrosine kinase ABL1. Interacts with tyrosine kinase TEC. Interacts with CSF1R. Interacts (via N-terminus) with SH3YL1 (via SH3 domain). Interacts with FCRL6 (tyrosine phosphorylated form). Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via ITIM). Interacts with NEDD9/HEF1.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Membrane. Cell projection. Filopodium. Lamellipodium. Basal cell membrane. Nucleus. Nucleus speckle. Spindle pole.

Tissue specificity. Widely expressed, most prominently in skeletal muscle, heart and brain. Present in platelets. Expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes.

Post-translational modifications. Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as insulin, growth factors such as EGF or PDGF, chemokines, integrin ligands and hypertonic and oxidative stress. May be phosphorylated upon IgG receptor FCGR2B-binding. Phosphorylated at Tyr-986 following cell attachment and spreading. Phosphorylated at Tyr-1162 following EGF signaling pathway stimulation. Phosphorylated at Thr-958 in response to PDGF.

Disease relevance. Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent. Opsismodysplasia (OPSMD) [MIM:258480] A rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with very delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane. Enzymatic activity is enhanced in the presence of phosphatidylserine.

Domain organisation. The SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or FCGR2A. It also mediates the interaction with p130Cas/BCAR1. The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain.

Induction. By bacterial lipopolysaccharides (LPS).

Miscellaneous. Its ability to confer resistance to dietary obesity suggests that it may serve as a possible therapeutic target in cases of type 2 diabetes and obesity.

Similarity. Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15357-1	1	yes
O15357-2	2

RefSeq proteins (1): NP_001558* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000300	IPPc	Domain
IPR000980	SH2	Domain
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR057509	C2_SHIP1-2_2nd	Domain
IPR057510	C2_SHIP1-2_first	Domain

Pfam: PF00017, PF00536, PF22669, PF24147, PF24150

Enzyme classification (BRENDA):

• EC 3.1.3.56 — inositol-polyphosphate 5-phosphatase (BRENDA: 35 organisms, 62 substrates, 55 inhibitors, 44 Km, 15 kcat entries)
• EC 3.1.3.86 — phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase (BRENDA: 6 organisms, 16 substrates, 55 inhibitors, 12 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-MYO-INOSITOL 1,4,5-TRISPHOSPHATE	0.001–0.32	19
5-DIPHOSPHOINOSITOL 1,2,3,4,6-PENTAKISPHOSPHATE	0.007–0.0481	11
D-MYO-INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	0.0008–0.019	7
1-PHOSPHATIDYL-1D-MYO-INOSITOL 3,4,5-TRISPHOSPHA	0.001–0.088	5
1-PHOSPHATIDYL-1D-MYO-INOSITOL 4,5-BISPHOSPHATE	0.0316–0.1	3
INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	0.082–0.126	3
1,5-BISDIPHOSPHOINOSITOL 2,3,4,6-TETRAKISPHOSPHA	0.0101	1
5-DIPHOSPHOINOSITOL 1,3,4,6-TETRAKISPHOSPHATE	0.0568	1
7-METHYL-6-THIOGUANOSINE	0.056	1
1D-MYO-INOSITOL 1,3,4,5-TETRAKISPHOSPHATE	0.125	1

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + phosphate (RHEA:25528)
• 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + phosphate (RHEA:43548)
• 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) + phosphate (RHEA:43556)

UniProt features (104 total): strand 35, helix 19, modified residue 12, sequence variant 9, compositionally biased region 8, turn 6, mutagenesis site 5, domain 2, region of interest 2, sequence conflict 2, short sequence motif 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
5OKP	X-RAY DIFFRACTION	1.85
5OKO	X-RAY DIFFRACTION	1.94
5OKM	X-RAY DIFFRACTION	1.96
4A9C	X-RAY DIFFRACTION	2.1
6SQU	X-RAY DIFFRACTION	2.27
6SRR	X-RAY DIFFRACTION	2.45
5OKN	X-RAY DIFFRACTION	2.65
3NR8	X-RAY DIFFRACTION	2.8
2K4P	SOLUTION NMR
2KSO	SOLUTION NMR
2MK2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15357-F1	70.75	0.39

Functional residue map

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

Post-translational modifications (12): 132, 165, 241, 352, 886, 890, 958, 986, 1131, 1135, 1162, 1257

Mutagenesis-validated functional residues (5):

Position	Phenotype
47	abolishes interaction with p130cas/bcar1 and its ability to induce increased adhesion. abolishes phosphorylation upon fc
140–141	abolishes interaction with sh3yl1.
607	abolishes enzyme activity but not phosphorylation upon fcgr2a clustering.
958	reduces pdgf-stimulated tyrosine phosphorylation and association with shc1.
986–987	inducer a strong reduction of phosphorylation upon re-plating on collagen i.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-912526	Interleukin receptor SHC signaling
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1430728	Metabolism
R-HSA-1483249	Inositol phosphate metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-168256	Immune System
R-HSA-449147	Signaling by Interleukins
R-HSA-451927	Interleukin-2 family signaling
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 513 (showing top): GOBP_LIPID_MODIFICATION, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, DORSAM_HOXA9_TARGETS_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, NKX25_02, GOBP_SPINDLE_LOCALIZATION, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, AP4_Q6, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (23): establishment of mitotic spindle orientation (GO:0000132), endochondral ossification (GO:0001958), immune system process (GO:0002376), glucose metabolic process (GO:0006006), phosphatidylinositol biosynthetic process (GO:0006661), endocytosis (GO:0006897), apoptotic process (GO:0006915), actin filament organization (GO:0007015), cell adhesion (GO:0007155), negative regulation of cell population proliferation (GO:0008285), post-embryonic development (GO:0009791), gene expression (GO:0010467), negative regulation of gene expression (GO:0010629), response to insulin (GO:0032868), regulation of protein localization (GO:0032880), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative regulation of insulin-like growth factor receptor signaling pathway (GO:0043569), phosphatidylinositol dephosphorylation (GO:0046856), regulation of immune response (GO:0050776), ERK1 and ERK2 cascade (GO:0070371), ruffle assembly (GO:0097178), regulation of actin filament organization (GO:0110053), lipid metabolic process (GO:0006629)

GO Molecular Function (8): actin binding (GO:0003779), inositol-polyphosphate 5-phosphatase activity (GO:0004445), SH3 domain binding (GO:0017124), phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity (GO:0034485), SH2 domain binding (GO:0042169), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791)

GO Cellular Component (13): spindle pole (GO:0000922), nucleus (GO:0005634), Golgi apparatus (GO:0005794), cytosol (GO:0005829), basal plasma membrane (GO:0009925), nuclear speck (GO:0016607), lamellipodium (GO:0030027), filopodium (GO:0030175), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Cytokine Signaling in Immune system	2
Metabolism	2
Signaling by Interleukins	2
PI Metabolism	1
Inositol phosphate metabolism	1
Interleukin-2 family signaling	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Immune System	1
Phospholipid metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
phosphatidylinositol metabolic process	2
protein domain specific binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
replacement ossification	1
endochondral bone morphogenesis	1
biological_process	1
hexose metabolic process	1
biosynthetic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
multicellular organism development	1
multicellular organismal process	1
macromolecule biosynthetic process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
response to peptide hormone	1
intracellular protein localization	1
regulation of localization	1
intracellular signaling cassette	1
negative regulation of signal transduction	1
regulation of insulin-like growth factor receptor signaling pathway	1
insulin-like growth factor receptor signaling pathway	1
phospholipid dephosphorylation	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INPPL1	EPHA2	P29317	982
INPPL1	SHC1	P29353	889
INPPL1	BCAR1	P56945	847
INPPL1	RAPH1	Q70E73	832
INPPL1	AKT1	P31749	808
INPPL1	FLNB	O75369	806
INPPL1	FNBP1	Q96RU3	758
INPPL1	SRC	P12931	723
INPPL1	FCGR2B	P31994	715
INPPL1	CD2AP	Q9Y5K6	692
INPPL1	ARAP3	Q8WWN8	690
INPPL1	UBASH3B	Q8TF42	681
INPPL1	FLNC	Q14315	677
INPPL1	ITSN1	Q15811	672
INPPL1	CBL	P22681	661

IntAct

203 interactions, top by confidence:

A	B	Type	Score
CD244	SH2D1B	psi-mi:“MI:0914”(association)	0.690
DPYSL5	DPYSL4	psi-mi:“MI:0914”(association)	0.640
MILR1	INPPL1	psi-mi:“MI:0914”(association)	0.640
PCYT2	INPPL1	psi-mi:“MI:0915”(physical association)	0.640
PCYT2	INPPL1	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
INPPL1	ITSN1	psi-mi:“MI:0915”(physical association)	0.600
ITSN1	INPPL1	psi-mi:“MI:0915”(physical association)	0.600
ITSN1	INPPL1	psi-mi:“MI:0403”(colocalization)	0.600
INPPL1	SORBS1	psi-mi:“MI:0915”(physical association)	0.580
SORBS1	INPPL1	psi-mi:“MI:0915”(physical association)	0.580
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
DYDC2	INPPL1	psi-mi:“MI:0914”(association)	0.560
INPPL1	DYDC2	psi-mi:“MI:0915”(physical association)	0.560
CIAO3	INPPL1	psi-mi:“MI:0914”(association)	0.530

BioGRID (289): INPPL1 (Affinity Capture-RNA), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), INPPL1 (Co-fractionation), INPPL1 (Co-fractionation), INPPL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NFE2, A0FI79, B1AVH7, B5DFA1, D2H0G5, D7PF45, O00750, O15357, O70143, P29353, P97573, P98083, Q00IB7, Q0IIE2, Q15678, Q16825, Q17R13, Q2I6J0, Q2I6J1, Q2V2M9, Q5JV73, Q5M824, Q5R7W7, Q5U2X5, Q61120, Q62130, Q62136, Q62728, Q62925, Q69Z98, Q6P4S2, Q6P549, Q80TI1, Q8AY68, Q8BMC3, Q8BYW1, Q8IWQ3, Q8K245, Q92529, Q92835

Diamond homologs: A0A8I3NFE2, A0FI79, A0JNB0, A1Y2K1, A6QLK6, B2RZ59, B5KFD7, D3ZGS3, D7PF45, F1RDG9, G5ECJ6, O14306, O14796, O15357, O35324, O60880, O88890, O88900, P00519, P00520, P00521, P00522, P03949, P06239, P06241, P09851, P0CE43, P10447, P17713, P20936, P29350, P29351, P32019, P34370, P39688, P42684, P42685, P42686, P50904, P53356

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
INPPL1	down-regulates	CBLC	binding
INPPL1	up-regulates	MAPK8IP1
INPPL1	down-regulates	AKT
INPPL1	down-regulates	PIP3	“chemical modification”
INPPL1	down-regulates	AKT1
SRC	up-regulates	INPPL1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
Downstream signal transduction	5	22.7×	5e-04
Clathrin-mediated endocytosis	10	10.2×	3e-05
Cargo recognition for clathrin-mediated endocytosis	8	10.0×	4e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — UCEC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	15
Uncertain significance	317
Likely benign	309
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069020	NM_001567.4(INPPL1):c.3565C>T (p.Gln1189Ter)	Pathogenic
1074745	NM_001567.4(INPPL1):c.2557del (p.Phe852_Leu853insTer)	Pathogenic
1323117	NM_001567.4(INPPL1):c.306C>G (p.Tyr102Ter)	Pathogenic
1430827	NM_001567.4(INPPL1):c.970_979dup (p.Gly327fs)	Pathogenic
1454034	NM_001567.4(INPPL1):c.2927dup (p.Pro977fs)	Pathogenic
1457946	NM_001567.4(INPPL1):c.2845C>T (p.Arg949Ter)	Pathogenic
1457958	NC_000011.9:g.(?71936029)(71936230_?)del	Pathogenic
1709919	NM_001567.4(INPPL1):c.3562dup (p.Leu1188fs)	Pathogenic
235826	NM_001567.4(INPPL1):c.2071C>T (p.Arg691Trp)	Pathogenic
2782479	NM_001567.4(INPPL1):c.3385_3386insGCTGCTGCAGATGGCCAAGA (p.Thr1129fs)	Pathogenic
3244741	NC_000011.9:g.(?71935411)(71943899_?)del	Pathogenic
3244742	NC_000011.9:g.(?71946389)(71948539_?)del	Pathogenic
39475	NM_001567.4(INPPL1):c.768del (p.Glu258fs)	Pathogenic
39476	NM_001567.4(INPPL1):c.2415+1G>A	Pathogenic
39477	NM_001567.4(INPPL1):c.1975C>T (p.Pro659Ser)	Pathogenic
39478	NM_001567.4(INPPL1):c.278_282del (p.Gln93fs)	Pathogenic
39479	NM_001567.4(INPPL1):c.1201C>T (p.Arg401Trp)	Pathogenic
39480	NM_001567.4(INPPL1):c.2164T>A (p.Phe722Ile)	Pathogenic
39481	NM_001567.4(INPPL1):c.94_121del (p.Glu32fs)	Pathogenic
431058	NM_001567.4(INPPL1):c.1845dup (p.Ile616fs)	Pathogenic
4697586	NM_001567.4(INPPL1):c.3403_3404insG (p.Tyr1135Ter)	Pathogenic
4711925	NM_001567.4(INPPL1):c.3222del (p.Pro1075fs)	Pathogenic
4723107	NM_001567.4(INPPL1):c.776del (p.Gln259fs)	Pathogenic
4730457	NM_001567.4(INPPL1):c.803del (p.Leu268fs)	Pathogenic
4811265	NM_001567.4(INPPL1):c.3638_3639del (p.Arg1212_Tyr1213insTer)	Pathogenic
931442	NM_001567.4(INPPL1):c.939+1G>A	Pathogenic
1029357	NM_001567.4(INPPL1):c.3549_3550insA (p.Glu1184fs)	Likely pathogenic
1224314	NM_001567.4(INPPL1):c.3057dup (p.Thr1020fs)	Likely pathogenic
1324584	NM_001567.4(INPPL1):c.2356C>T (p.Gln786Ter)	Likely pathogenic
1339494	NM_001567.4(INPPL1):c.3466del (p.Arg1156fs)	Likely pathogenic

SpliceAI

4424 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72225162:GTCCT:G	donor_gain	1.0000
11:72225163:TCCT:T	donor_gain	1.0000
11:72225166:TGTG:T	donor_loss	1.0000
11:72225167:G:GG	donor_gain	1.0000
11:72225168:T:G	donor_loss	1.0000
11:72228335:T:A	acceptor_gain	1.0000
11:72228338:T:A	acceptor_gain	1.0000
11:72228346:A:AG	acceptor_gain	1.0000
11:72228347:G:GG	acceptor_gain	1.0000
11:72228347:GA:G	acceptor_gain	1.0000
11:72228496:CAG:C	donor_loss	1.0000
11:72228498:GGTAC:G	donor_loss	1.0000
11:72228499:G:T	donor_loss	1.0000
11:72229086:A:AG	acceptor_gain	1.0000
11:72229086:AAAGT:A	acceptor_gain	1.0000
11:72229087:A:G	acceptor_gain	1.0000
11:72229088:A:AG	acceptor_gain	1.0000
11:72229089:G:GA	acceptor_gain	1.0000
11:72229089:GT:G	acceptor_gain	1.0000
11:72229463:A:AG	acceptor_gain	1.0000
11:72229464:G:GG	acceptor_gain	1.0000
11:72229750:A:T	donor_gain	1.0000
11:72229921:CAG:C	acceptor_loss	1.0000
11:72229922:A:AC	acceptor_loss	1.0000
11:72229922:A:AG	acceptor_gain	1.0000
11:72229923:G:GG	acceptor_gain	1.0000
11:72229923:G:T	acceptor_loss	1.0000
11:72229985:G:GG	donor_gain	1.0000
11:72230117:ACAGG:A	acceptor_loss	1.0000
11:72230118:CAGGT:C	acceptor_loss	1.0000

AlphaMissense

8133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72225109:G:A	G42D	1.000
11:72225109:G:T	G42V	1.000
11:72225114:T:C	F44L	1.000
11:72225116:C:A	F44L	1.000
11:72225116:C:G	F44L	1.000
11:72225118:T:C	L45P	1.000
11:72225121:T:A	V46D	1.000
11:72225157:T:A	L58H	1.000
11:72225157:T:C	L58P	1.000
11:72225161:C:G	C59W	1.000
11:72225166:T:C	L61P	1.000
11:72228212:T:G	Y69D	1.000
11:72228219:T:A	I71N	1.000
11:72228219:T:C	I71T	1.000
11:72228394:T:A	L98H	1.000
11:72228394:T:C	L98P	1.000
11:72229191:T:C	L207P	1.000
11:72229712:T:C	L268P	1.000
11:72230182:T:C	L334P	1.000
11:72230371:T:C	L367P	1.000
11:72230378:G:C	K369N	1.000
11:72230378:G:T	K369N	1.000
11:72230401:T:C	L377P	1.000
11:72230455:T:C	F395S	1.000
11:72230818:T:C	L407P	1.000
11:72230884:G:A	G429D	1.000
11:72230889:T:A	W431R	1.000
11:72230889:T:C	W431R	1.000
11:72230894:C:A	N432K	1.000
11:72230894:C:G	N432K	1.000

dbSNP variants (sampled 300 via entrez): RS1000207551 (11:72228509 G>A,T), RS1000298460 (11:72226054 T>A,C), RS1000392731 (11:72226230 G>A), RS1000602331 (11:72222974 T>C), RS1000631016 (11:72227082 C>G), RS1000717798 (11:72234053 C>T), RS1000911361 (11:72222581 T>C,G), RS1001108173 (11:72227725 C>T), RS1001283214 (11:72226051 C>A,G), RS1001319589 (11:72226173 A>G,T), RS1001395700 (11:72225055 G>A), RS1001545408 (11:72238735 C>A), RS1001879206 (11:72237687 G>A), RS1001989178 (11:72230856 G>A), RS1002098434 (11:72237498 C>G,T)

Disease associations

OMIM: gene MIM:600829 | disease phenotypes: MIM:258480

GenCC curated gene-disease

Disease	Classification	Inheritance
opsismodysplasia	Definitive	Autosomal recessive
schneckenbecken dysplasia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
opsismodysplasia	Definitive	AR

Mondo (2): opsismodysplasia (MONDO:0009785), schneckenbecken dysplasia (MONDO:0010013)

Orphanet (1): Opsismodysplasia (Orphanet:2746)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000117	Renal phosphate wasting
HP:0000175	Cleft palate
HP:0000239	Large fontanelles
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000520	Proptosis
HP:0000586	Shallow orbits
HP:0000592	Blue sclerae
HP:0000637	Long palpebral fissure
HP:0000767	Pectus excavatum
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000882	Hypoplastic scapulae
HP:0000895	Lateral clavicle hook
HP:0000907	Anterior rib cupping
HP:0000922	Posterior rib cupping
HP:0000944	Abnormal metaphysis morphology
HP:0000946	Hypoplastic ilia
HP:0000947	Dumbbell-shaped long bone
HP:0000969	Edema

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005846_11	Heart rate response to recovery post exercise (10 sec)	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009185	heart rate response to recovery post exercise

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537122	Opsismodysplasia (supp.)
C536637	Schneckenbecken dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331064 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 14,459 (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
CHEMBL601719	CRIZOTINIB	4	14,403

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Inositol polyphosphate phosphatases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
AS1949490	Inhibition	6.21	pIC50

Binding affinities (BindingDB)

47 measured of 50 human assays (50 total across all organisms); most potent 47 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-[3-[[2-[4-(4-cyanophenyl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	220 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-[4-(3-cyanophenyl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	310 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-2-[3-[[2-[2-[5-(2-hydroxyethyl)furan-2-yl]anilino]-2-oxoacetyl]amino]phenyl]-3-iodo-1-methylindole-5-carboxylic acid	IC50	370 nM	US-9844535: SHP2 inhibitors and methods of treating autoimmune and/or glomerulonephritis-associated diseases using SHP2 inhibitors
6-hydroxy-2-[3-[[2-[2-[5-(hydroxymethyl)furan-2-yl]anilino]-2-oxoacetyl]amino]phenyl]-3-iodo-1-methylindole-5-carboxylic acid	IC50	370 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-[3-(furan-2-yl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	380 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-[3-(4-cyanophenyl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	420 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(4-phenylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	620 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(3-thiophen-3-ylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	630 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(3-chloro-4-phenylmethoxyanilino)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	660 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-[(6-bromo-1,3-benzothiazol-2-yl)amino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	760 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(3-phenylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	770 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(3-phenylmethoxyanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	860 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(5-bromo-2,3-dihydroindol-1-yl)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1050 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-2-[3-[[2-(4-iodoanilino)-2-oxoacetyl]amino]phenyl]-1-methylindole-5-carboxylic acid	IC50	1200 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-[2-(2,7a-dihydro-1H-benzimidazol-2-yl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1250 nM	US-9844535: SHP2 inhibitors and methods of treating autoimmune and/or glomerulonephritis-associated diseases using SHP2 inhibitors
2-[3-[[2-[2-(1H-benzimidazol-2-yl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1250 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(1,3-benzothiazol-2-ylamino)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1350 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(3-chloroanilino)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1460 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-2-[3-[[2-(4-imidazol-1-ylanilino)-2-oxoacetyl]amino]phenyl]-3-iodo-1-methylindole-5-carboxylic acid	IC50	1490 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[4-[(3-chloro-4-phenylmethoxyphenyl)carbamoyl]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1600 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-[4-chloro-3-(trifluoromethyl)anilino]-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1760 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-[(5-phenyl-1,3,4-thiadiazol-2-yl)amino]acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	1790 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(4-fluoroanilino)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	1840 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-(4-thiophen-3-ylanilino)butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	2300 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(1,3-thiazol-2-ylamino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	2310 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-[3-(trifluoromethoxy)anilino]acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	2390 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[4-[(3-phenylmethoxyphenyl)carbamoyl]phenyl]indole-5-carboxylic acid	IC50	2400 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(3-bromoanilino)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	2730 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(4-thiophen-3-ylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	2900 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-(4-phenoxyanilino)butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	3600 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[4-(1,3-benzodioxol-5-ylmethylcarbamoyl)phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	4200 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-(3-phenylmethoxyanilino)butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	4500 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[2-(3-fluoroanilino)-2-oxoacetyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	4660 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[4-oxo-4-(3-phenylmethoxyanilino)butyl]indole-5-carboxylic acid	IC50	5000 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[4-(3-chloro-4-phenylmethoxyanilino)-4-oxobutanoyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	5000 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-(3-phenylanilino)butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	5300 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-2-[3-[[2-(3-iodoanilino)-2-oxoacetyl]amino]phenyl]-1-methylindole-5-carboxylic acid	IC50	5420 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
PTP Inhibitor XXXI, II-B08	IC50	5500 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[4-(5-bromo-2,3-dihydroindol-1-yl)-4-oxobutanoyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	7200 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-[4-(trifluoromethoxy)anilino]butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	8600 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-(4-carboxyphenyl)-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	9200 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-(4-propan-2-ylanilino)butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	10700 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[4-(1,3-benzodioxol-5-ylmethylamino)-4-oxobutyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	12600 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-[[4-(1,3-benzodioxol-5-ylmethylamino)-4-oxobutanoyl]amino]phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	14000 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-(oxaloamino)phenyl]indole-5-carboxylic acid	IC50	14400 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
6-hydroxy-3-iodo-1-methyl-2-[3-[[4-oxo-4-(1,3-thiazol-2-ylamino)butanoyl]amino]phenyl]indole-5-carboxylic acid	IC50	26000 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
2-[3-(3-carboxypropanoylamino)phenyl]-6-hydroxy-3-iodo-1-methylindole-5-carboxylic acid	IC50	56000 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

ChEMBL bioactivities

47 potent at pChembl≥5 of 102 total, top 45 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.64	IC50	23	nM	CHEMBL5087243
7.57	IC50	27	nM	CHEMBL5078323
7.54	IC50	29	nM	CHEMBL5092991
7.51	IC50	31	nM	CHEMBL5080660
7.21	IC50	61	nM	CHEMBL5081948
6.75	Kd	175.9	nM	CHEMBL3752910
6.44	ED50	364	nM	CHEMBL3752910
6.36	Ki	440	nM	CHEMBL2337806
6.36	Ki	440	nM	CHEMBL4282693
6.31	Kd	487.7	nM	CHEMBL5653589
6.21	IC50	620	nM	CHEMBL2337806
6.16	IC50	700	nM	CHEMBL5087243
6.05	IC50	900	nM	CHEMBL5078323
6.00	IC50	1010	nM	CHEMBL4454154
6.00	IC50	1000	nM	CHEMBL5087243
6.00	ED50	1009	nM	CHEMBL5653589
5.99	IC50	1020	nM	CHEMBL4538474
5.96	IC50	1100	nM	CHEMBL2337807
5.82	IC50	1500	nM	CHEMBL2337806
5.81	IC50	1540	nM	CHEMBL5092487
5.80	IC50	1600	nM	CHEMBL5078323
5.75	IC50	1800	nM	CHEMBL1601846
5.70	IC50	2000	nM	CHEMBL4282693
5.70	IC50	2000	nM	CHEMBL4287228
5.64	IC50	2300	nM	CHEMBL23552
5.60	IC50	2500	nM	CHEMBL5081948
5.58	IC50	2600	nM	CHEMBL1601846
5.57	IC50	2700	nM	CHEMBL5080660
5.56	IC50	2780	nM	CHEMBL595349
5.50	IC50	3200	nM	CHEMBL4285629
5.47	IC50	3400	nM	CHEMBL5092991
5.44	IC50	3600	nM	CHEMBL5092991
5.43	IC50	3690	nM	CHEMBL4286790
5.43	IC50	3670	nM	CHEMBL4286681
5.31	Ki	4900	nM	CHEMBL5080660
5.30	IC50	5000	nM	CHEMBL6144748
5.26	IC50	5500	nM	CRIZOTINIB
5.26	IC50	5500	nM	PURPUROGALLIN
5.23	IC50	5900	nM	CHEMBL4285693
5.22	IC50	6000	nM	CHEMBL234338
5.20	IC50	6250	nM	CHEMBL4473747
5.15	IC50	7020	nM	CHEMBL4473747
5.14	IC50	7300	nM	PURPUROGALLIN
5.07	IC50	8520	nM	CHEMBL4277817
5.03	IC50	9280	nM	CHEMBL4286383

PubChem BioAssay actives

44 with measured affinity, of 237 total; 27 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
[2,3-diphosphonooxy-5-(3,4,5-triphosphonooxyphenyl)phenyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	0.0230	uM
[2,4-diphosphonooxy-5-(2,4,5-triphosphonooxyphenyl)phenyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	0.0270	uM
[2-(3,5-diphosphonooxyphenyl)-3,5-diphosphonooxyphenyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	0.0290	uM
[2,4-diphosphonooxy-5-[2-(2,4,5-triphosphonooxyphenoxy)ethoxy]phenyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	0.0310	uM
[4-fluoro-5-(2-fluoro-4,5-diphosphonooxyphenyl)-2-phosphonooxyphenyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	0.0610	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148592: Binding affinity to human INPPL1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1759	uM
3-[(4-chlorophenyl)methoxy]-N-[(1S)-1-phenylethyl]thiophene-2-carboxamide	1829590: Inhibition of human SHIP2 (419 to 732 residues) expressed in Escherichia coli by malachite green phosphate assay	ki	0.4400	uM
3-[(2,4-dichlorophenyl)methoxy]-N-[(2,6-difluorophenyl)methyl]thiophene-2-carboxamide	1829590: Inhibition of human SHIP2 (419 to 732 residues) expressed in Escherichia coli by malachite green phosphate assay	ki	0.4400	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148592: Binding affinity to human INPPL1 incubated for 45 mins by Kinobead based pull down assay	kd	0.4877	uM
(2,3,5-triphosphonooxyphenyl) dihydrogen phosphate	1547657: Displacement of 2FAMInsP5 from recombinant human N-terminal His-tagged SHIP2 (419 to 832 residues) expressed in Escherichia coli Rosetta2 (DE3) cells by fluorescence polarization assay	ic50	1.0100	uM
(2,4,5-triphosphonooxyphenyl) dihydrogen phosphate	1547657: Displacement of 2FAMInsP5 from recombinant human N-terminal His-tagged SHIP2 (419 to 832 residues) expressed in Escherichia coli Rosetta2 (DE3) cells by fluorescence polarization assay	ic50	1.0200	uM
N-[5-[1-(3,4-dichlorophenyl)-5-(4-fluorophenyl)pyrazol-3-yl]-2-pyridinyl]-N’,N’-di(propan-2-yl)ethane-1,2-diamine	734683: Inhibition of SHIP2 (unknown origin)	ic50	1.1000	uM
[4-[2-(3,4-diphosphonooxyphenoxy)ethoxy]-2-phosphonooxyphenyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	1.5400	uM
2,3,9,10-tetrahydroxypyrano[3,2-c]isochromene-6,8-dione	1829586: Inhibition of human SHIP2 catalytic domain (419 to 832 residues) phosphatase activity assessed as phosphate release using Ins(1,3,4,5)P4 as substrate incubated for 20 mins measured using microplate reader	ic50	1.8000	uM
5-[5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridinyl]pyrimidin-2-amine	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	2.0000	uM
[(1R,2S,4S,5S)-2,4-dihydroxy-3,5,6-triphosphonooxycyclohexyl] dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	2.3000	uM
(2,3,4-triphosphonooxyphenyl) dihydrogen phosphate	1547657: Displacement of 2FAMInsP5 from recombinant human N-terminal His-tagged SHIP2 (419 to 832 residues) expressed in Escherichia coli Rosetta2 (DE3) cells by fluorescence polarization assay	ic50	2.7800	uM
5-[5-[(2,4-dichlorophenyl)methoxy]-3-pyridinyl]thiophene-2-carbonitrile	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	3.2000	uM
5-[5-[(2,4-dichlorophenyl)methoxy]-3-pyridinyl]pyridin-2-amine	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	3.6700	uM
3-[(2,4-dichlorophenyl)methoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridine	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	3.6900	uM
Crizotinib	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	5.5000	uM
2,3,4,6-tetrahydroxybenzo[7]annulen-5-one	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	5.5000	uM
5-[5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridinyl]thiophene-2-carbonitrile	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	5.9000	uM
5,6,7,8-tetrahydroxy-2-(4-hydroxyphenyl)chromen-4-one	1829586: Inhibition of human SHIP2 catalytic domain (419 to 832 residues) phosphatase activity assessed as phosphate release using Ins(1,3,4,5)P4 as substrate incubated for 20 mins measured using microplate reader	ic50	6.0000	uM
(2,4-diphosphonooxyphenyl) dihydrogen phosphate	1829585: Inhibition of 2-FAM-InsP5 binding to human SHIP2 catalytic domain (419 to 832 residues) assessed as change in polarization by fluorescence polarization based displacement assay	ic50	6.2500	uM
5-[5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridinyl]-2-piperazin-1-ylpyrimidine	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	8.5200	uM
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridine	1407756: Inhibition of SHIP2 (unknown origin) assessed as decrease in PIP2 production using PtdIns(3,4,5)P3 as substrate preincubated for 20 mins followed by substrate addition measured for 50 mins by malachite green staining based assay	ic50	9.2800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation, affects expression	4
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Arsenic	decreases expression, increases abundance, increases expression, decreases methylation, affects cotreatment	3
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
AZD5991	decreases expression	1
tapotoclax	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
glycidyl methacrylate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
tanshinone	increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
ICG 001	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1

ChEMBL screening assays

38 unique, capped per target: 38 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2343088	Binding	Inhibition of SHIP2 (unknown origin)	Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5’-phosphatase 2 (SHIP2). — Eur J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1WX	Abcam A-549 INPPL1 KO	Cancer cell line	Male
CVCL_D2B8	Abcam HCT 116 INPPL1 KO	Cancer cell line	Male
CVCL_SS74	HAP1 INPPL1 (-) 1	Cancer cell line	Male
CVCL_SS75	HAP1 INPPL1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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