SOS1

Summary

SOS1 (SOS Ras/Rac guanine nucleotide exchange factor 1, HGNC:11187) is a protein-coding gene on chromosome 2p22.1, encoding Son of sevenless homolog 1 (Q07889). Promotes the exchange of Ras-bound GDP by GTP. In precision oncology, HGF EXPRESSION confers sensitivity to MET Tyrosine Kinase Inhibitor SGX523 in Glioblastoma (CIViC Level D). It is a selective cancer dependency (DepMap: 15.7% of cell lines).

This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4.

Source: NCBI Gene 6654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 2,126 total — 27 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 101
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 15.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11187
Approved symbol	SOS1
Name	SOS Ras/Rac guanine nucleotide exchange factor 1
Location	2p22.1
Locus type	gene with protein product
Status	Approved
Aliases	HGF, GF1
Ensembl gene	ENSG00000115904
Ensembl biotype	protein_coding
OMIM	182530
Entrez	6654

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 protein_coding, 8 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000395038, ENST00000402219, ENST00000451331, ENST00000461545, ENST00000469581, ENST00000472480, ENST00000474390, ENST00000685279, ENST00000685782, ENST00000686849, ENST00000688043, ENST00000688189, ENST00000689668, ENST00000690514, ENST00000690679, ENST00000690876, ENST00000691229, ENST00000692089, ENST00000692227, ENST00000692620, ENST00000913800, ENST00000913801

RefSeq mRNA: 3 — MANE Select: NM_005633 NM_001382394, NM_001382395, NM_005633

CCDS: CCDS1802, CCDS92739

Canonical transcript exons

ENST00000402219 — 23 exons

Exon	Start	End
ENSE00000748058	38987473	38987591
ENSE00000748060	38989270	38989314
ENSE00000748062	38995123	38995387
ENSE00000748064	38996922	38997038
ENSE00000748066	38997253	38997425
ENSE00000748070	39007031	39007193
ENSE00000748072	39010584	39010703
ENSE00000748074	39012126	39012348
ENSE00000748075	39013460	39013563
ENSE00000748076	39013867	39013989
ENSE00000748077	39014765	39014846
ENSE00000748078	39022570	39023225
ENSE00001555885	38981549	38986315
ENSE00002451515	39058673	39058804
ENSE00002459474	39054614	39054823
ENSE00002459913	39056702	39056866
ENSE00002472890	39051144	39051287
ENSE00002729053	39120336	39121051
ENSE00003482434	39067628	39067753
ENSE00003572011	39024010	39024137
ENSE00003618515	39035212	39035310
ENSE00003629205	39006412	39006529
ENSE00003663972	39035390	39035500

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 94.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.9846 / max 417.8463, expressed in 1820 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27916	26.5525	1818
27913	0.5573	215
27914	0.4028	127
27903	0.1899	109
27912	0.1750	67
27911	0.1023	46
27902	0.0048	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	94.79	gold quality
jejunal mucosa	UBERON:0000399	93.50	gold quality
tendon of biceps brachii	UBERON:0008188	93.41	gold quality
trigeminal ganglion	UBERON:0001675	93.32	gold quality
dorsal root ganglion	UBERON:0000044	92.88	gold quality
jejunum	UBERON:0002115	92.79	gold quality
calcaneal tendon	UBERON:0003701	92.79	gold quality
tendon	UBERON:0000043	92.37	gold quality
seminal vesicle	UBERON:0000998	91.43	gold quality
corpus callosum	UBERON:0002336	90.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.81	gold quality
adrenal tissue	UBERON:0018303	90.78	gold quality
pylorus	UBERON:0001166	90.71	gold quality
pericardium	UBERON:0002407	90.71	gold quality
adipose tissue	UBERON:0001013	90.65	gold quality
connective tissue	UBERON:0002384	90.54	gold quality
mammary duct	UBERON:0001765	90.34	gold quality
skin of hip	UBERON:0001554	90.10	gold quality
duodenum	UBERON:0002114	90.06	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.03	gold quality
mucosa of stomach	UBERON:0001199	90.01	gold quality
biceps brachii	UBERON:0001507	90.00	gold quality
medial globus pallidus	UBERON:0002477	89.90	gold quality
urethra	UBERON:0000057	89.88	gold quality
saphenous vein	UBERON:0007318	89.68	gold quality
right ovary	UBERON:0002118	89.62	gold quality
cortical plate	UBERON:0005343	89.49	gold quality
endometrium	UBERON:0001295	89.47	gold quality
epithelium of mammary gland	UBERON:0003244	89.46	gold quality
left ovary	UBERON:0002119	89.43	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	26.44
E-MTAB-8142	yes	15.08
E-ANND-3	yes	6.25
E-MTAB-6524	no	143.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, EGR1, HOXD1

miRNA regulators (miRDB)

249 targeting SOS1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AN	99.97	70.91	2817

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 15.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1 (PMID:11868160)
• study of tandem histone folds in the structure of the N-terminal segment of the ras activator Son of Sevenless (PMID:14656442)
• p21Ras, hSOS1, and p120GAP are not involved in polycystic ovary disease (PMID:15010862)
• The full-length Grb2 proteins mediate negative regulation of the intrinsic Ras guanine-nucleotide exchange activity of hSos1. (PMID:16760435)
• In T cells, the SH2 domain of GRB2 binds phosphorylated tyrosines on the adaptor protein LAT and the GRB2 SH3 domains associate with the proline-rich regions of SOS1 and CBL. (PMID:16906159)
• increased fibroblast numbers and collagen matrix changes are associated with mutation [in hereditary gingival fibromatosis] (PMID:17062749)
• crystal structure of the Rem and Cdc25 domains of Sos1 determined at 2.0-A resolution in the absence of Ras (PMID:17075039)
• Missense mutations in SOS1 associated with Noonan syndrome. (PMID:17143282)
• SOS1 mutants as a major cause of Noonan syndrome. (PMID:17143285)
• The unusual RasGRP-SOS interplay results in sensitive and robust Ras activation that cannot be achieved with either activator alone. (PMID:17283063)
• it was concluded that SOS1 does not act as a proto-oncogene in juvenile myelomonocytic leukemia (PMID:17315019)
• The pleckstrin homology domain of human SOS1 seems to function as a sensor domain in detecting the prenylation status of Ras bound to the distal site of SOS1. (PMID:17437339)
• Our findings establish a crucial role for PLD2 in the coupling of extracellular signals to Sos-mediated Ras activation, and provide new insights into the spatial coordination of this activation event. (PMID:17486115)
• study reports that mutant SOS1 contributes an increased and sustained activation of ERK signaling in Hereditary gingival fibromatosis 1 fibroblasts under serum-starved conditions (PMID:17510059)
• SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome (PMID:17586837)
• findings suggest that SOS1 is not a significant human oncogene in most cancers. Furthermore, NS patients with SOS1 mutations may not be at increased risk of developing cancer (PMID:18064648)
• Study shows that SOS responds to the membrane density of Ras molecules, to their GTP loading and to the concentration of phosphatidylinositol-4,5-bisphosphate, and that the integration of these signals potentiates the release of autoinhibition. (PMID:18454158)
• Patients with SOS1 mutations range from Noonan syndrome to cardio-facio-cutaneous syndrome. (PMID:18651097)
• Structural basis of the differential binding of the SH3 domains of GRB2 and SOS1 are reported. (PMID:18778683)
• Mutational analysis of SOS1 gene in acute myeloid leukemia. (PMID:18972187)
• Mutations in the SOS1 are associated with Noonan syndrome. (PMID:19020799)
• Loss of MADD expression resulted in reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation (PMID:19289468)
• analysis of SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions (PMID:19352411)
• the involvement of SOS1 gene in a family with the Noonan-like/multiple giant cell lesion phenotype (PMID:19438935)
• The tandem SH3A and SH3B domains of Tks5 constitute a versatile module for the implementation of isoform-specific protein-protein interactions. (PMID:19464300)
• Enhanced expression of SOS1 is detected in prostate cancer epithelial cells from African-American men. (PMID:19724911)
• First report describing different tumor types in Noonan syndrome with germline SOS1 mutations. (PMID:19953625)
• The binding of Grb2 adaptor to its downstream partners Sos1 and Gab1 docker is under tight allosteric regulation. (PMID:20005866)
• A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway. (PMID:20030748)
• a new crystal structure of SOS at 3.2 A resolution was presented that contains the histone domain and the DH-PH unit in addition to the catalytic segment (SOSHDPC, residues 1-1049). (PMID:20133692)
• Sos-histone domain plays a critical role in governing the catalytic output of Sos through the coupling of membrane recruitment to the release of autoinhibition. (PMID:20133694)
• Noonan-like/multiple giant cell lesion syndrome with mutations in the SOS1 gene (PMID:20305546)
• Based on our results, it is possible that a subtle dysfunction (expression) of the SOS1 gene is involved in the development of the most common male reproductive tract disorder - unilateral or bilateral cryptorchidism (PMID:20389169)
• Noonan syndrome is due to a SOS1 missense mutation and rhabdomyosarcoma. (PMID:20607846)
• two unrelated patients with Noonan syndrome carrying the same heterozygous SOS1 missense mutation (c.1867T > A/p.F623I) (PMID:20673819)
• mutation analysis performed on RAF1, SOS1, and GRB2, in 24 Noonan syndrome patients previously found to be negative for PTPN11 and KRAS mutations; SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease (PMID:20683980)
• Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK. (PMID:20724475)
• This study investigated the regulation of the previously uncharacterized SOS1 gene promoter by the aryl hydrocarbon receptor and its ligands in HepG2 cells. (PMID:20950586)
• this report expanded the available information about the molecular diversity of SOS1 mutations underlying Noonan syndrome, and have provided a more comprehensive assessment of the clinical features associated with those molecular lesions. (PMID:21387466)
• The researchers found evidence that there were significant differences between the D2S441 locus in the Maghreb population and other populations. (PMID:21674833)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sos1	ENSDARG00000100503
mus_musculus	Sos1	ENSMUSG00000024241
rattus_norvegicus	Sos1	ENSRNOG00000007106

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), SOS2 (ENSG00000100485), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RAPGEF6 (ENSG00000158987), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

Son of sevenless homolog 1 — Q07889 (reviewed: Q07889)

All UniProt accessions (10): A0A8I5KP47, A0A8I5KV97, A0A8I5KWL0, A0A8I5KY52, A0A8I5QJ77, A0A8I5QJD1, A0A8I5QJF3, C9K0N6, Q07889, G5E9C8

UniProt curated annotations — full annotation on UniProt →

Function. Promotes the exchange of Ras-bound GDP by GTP. Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3/ERK1 in response to EGF. Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity.

Subunit / interactions. Interacts (via C-terminus) with GRB2 (via SH3 domain). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains). Interacts with phosphorylated LAT2. Interacts with NCK1 and NCK2. Part of a complex consisting of ABI1, EPS8 and SOS1. Interacts (Ser-1134 and Ser-1161 phosphorylated form) with YWHAB and YWHAE.

Tissue specificity. Expressed in gingival tissues.

Post-translational modifications. Phosphorylation at Ser-1134 and Ser-1161 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation.

Disease relevance. Fibromatosis, gingival, 1 (GINGF1) [MIM:135300] A form of hereditary gingival fibromatosis, a rare condition characterized by a slow, progressive overgrowth of the gingiva. The excess gingival tissue can cover part of or the entire crown, and can result in diastemas, teeth displacement, or retention of primary or impacted teeth. GINGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 4 (NS4) [MIM:610733] 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 NS4 have polyarticular villonodular synovitis. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q07889-1	1	yes
Q07889-2	2

RefSeq proteins (3): NP_001369323, NP_001369324, NP_005624* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001849	PH_domain	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR008937	Ras-like_GEF	Family
IPR009072	Histone-fold	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR019804	Ras_G-nucl-exch_fac_CS	Conserved_site
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00617, PF00618, PF00621, PF22697

UniProt features (167 total): helix 55, sequence variant 53, strand 22, turn 12, modified residue 8, domain 4, compositionally biased region 4, splice variant 3, mutagenesis site 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

91 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6V9M	X-RAY DIFFRACTION	1.65
6V9N	X-RAY DIFFRACTION	1.65
6D55	X-RAY DIFFRACTION	1.68
6D56	X-RAY DIFFRACTION	1.68
6V9L	X-RAY DIFFRACTION	1.7
6D59	X-RAY DIFFRACTION	1.7
6D5L	X-RAY DIFFRACTION	1.7
6Y44	X-RAY DIFFRACTION	1.71
7AVL	X-RAY DIFFRACTION	1.72
6CUO	X-RAY DIFFRACTION	1.73
6CUR	X-RAY DIFFRACTION	1.73
6BVI	X-RAY DIFFRACTION	1.75
6BVJ	X-RAY DIFFRACTION	1.75
6BVL	X-RAY DIFFRACTION	1.75
6D5E	X-RAY DIFFRACTION	1.75
6D5J	X-RAY DIFFRACTION	1.75
6V9J	X-RAY DIFFRACTION	1.76
6BVM	X-RAY DIFFRACTION	1.8
6BVK	X-RAY DIFFRACTION	1.8
6V9O	X-RAY DIFFRACTION	1.8
6D5H	X-RAY DIFFRACTION	1.8
6V94	X-RAY DIFFRACTION	1.8
6CUP	X-RAY DIFFRACTION	1.83
6V9F	X-RAY DIFFRACTION	1.85
5OVE	X-RAY DIFFRACTION	1.85
6SCM	X-RAY DIFFRACTION	1.87
9QFF	X-RAY DIFFRACTION	1.88
7AVT	X-RAY DIFFRACTION	1.88
8BE2	X-RAY DIFFRACTION	1.9
5OVD	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07889-F1	77.12	0.48

Antibody-complex structures (SAbDab): 2 — 8BE2, 8BE5

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 (8): 1078, 1082, 1134, 1161, 1178, 1210, 1229, 1275

Mutagenesis-validated functional residues (3):

Position	Phenotype
282	increases mapk3 phosphorylation in response to egf stimulation.
1134	loss of phosphorylation, disruption of interaction with ywhab and ywhae, and modest increase in the magnitude and durati
1161	loss of phosphorylation, disruption of interaction with ywhab and ywhae, and modest increase in the magnitude and durati

Function

Pathways and Gene Ontology

Reactome pathways

133 pathways

ID	Pathway
R-HSA-112412	SOS-mediated signalling
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1433559	Regulation of KIT signaling
R-HSA-167044	Signalling to RAS
R-HSA-179812	GRB2 events in EGFR signaling
R-HSA-180336	SHC1 events in EGFR signaling
R-HSA-186763	Downstream signal transduction
R-HSA-193648	NRAGE signals death through JNK
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-210993	Tie2 Signaling
R-HSA-2179392	EGFR Transactivation by Gastrin
R-HSA-2424491	DAP12 signaling
R-HSA-2428933	SHC-related events triggered by IGF1R
R-HSA-2730905	Role of LAT2/NTAL/LAB on calcium mobilization
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-354194	GRB2:SOS provides linkage to MAPK signaling for Integrins
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-428540	Activation of RAC1
R-HSA-5637810	Constitutive Signaling by EGFRvIII
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654704	SHC-mediated cascade:FGFR3
R-HSA-5654706	FRS-mediated FGFR3 signaling

MSigDB gene sets: 1292 (showing top): PID_BCR_5PATHWAY, PID_SHP2_PATHWAY, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, CREL_01, BIOCARTA_PTEN_PATHWAY, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT

GO Biological Process (38): B cell homeostasis (GO:0001782), hair follicle development (GO:0001942), response to ischemia (GO:0002931), cardiac atrium morphogenesis (GO:0003209), pericardium morphogenesis (GO:0003344), regulation of transcription by RNA polymerase II (GO:0006357), signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), Ras protein signal transduction (GO:0007265), vitellogenesis (GO:0007296), axon guidance (GO:0007411), insulin receptor signaling pathway (GO:0008286), fibroblast growth factor receptor signaling pathway (GO:0008543), Schwann cell development (GO:0014044), cytokine-mediated signaling pathway (GO:0019221), regulation of T cell differentiation in thymus (GO:0033081), positive regulation of Rac protein signal transduction (GO:0035022), multicellular organism growth (GO:0035264), Fc-epsilon receptor signaling pathway (GO:0038095), T cell activation (GO:0042110), regulation of cell population proliferation (GO:0042127), regulation of T cell proliferation (GO:0042129), myelination (GO:0042552), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), insulin-like growth factor receptor signaling pathway (GO:0048009), neurotrophin TRK receptor signaling pathway (GO:0048011), blood vessel morphogenesis (GO:0048514), B cell receptor signaling pathway (GO:0050853), leukocyte migration (GO:0050900), roof of mouth development (GO:0060021), eyelid development in camera-type eye (GO:0061029), heart trabecula morphogenesis (GO:0061384), midbrain morphogenesis (GO:1904693), regulation of pro-B cell differentiation (GO:2000973), lymphocyte homeostasis (GO:0002260), heart morphogenesis (GO:0003007), small GTPase-mediated signal transduction (GO:0007264), positive regulation of small GTPase mediated signal transduction (GO:0051057)

GO Molecular Function (8): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), epidermal growth factor receptor binding (GO:0005154), SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), protein heterodimerization activity (GO:0046982), molecular condensate scaffold activity (GO:0140693), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), neuronal cell body (GO:0043025), glutamatergic synapse (GO:0098978), GTPase complex (GO:1905360)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Fc epsilon receptor (FCERI) signaling	3
Signaling by ERBB2	2
Signaling by EGFR	2
IRS-mediated signalling	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Signaling by ERBB4	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by SCF-KIT	1
Signalling to ERKs	1
Signaling by PDGF	1
Cell death signalling via NRAGE, NRIF and NADE	1
Cell surface interactions at the vascular wall	1
Gastrin-CREB signalling pathway via PKC and MAPK	1
DAP12 interactions	1
IGF1R signaling cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor protein tyrosine kinase signaling pathway	2
GTPase regulator activity	2
cellular anatomical structure	2
lymphocyte homeostasis	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
response to stress	1
cardiac chamber morphogenesis	1
cardiac atrium development	1
morphogenesis of an epithelial sheet	1
embryonic morphogenesis	1
pericardium development	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ERBB signaling pathway	1
small GTPase-mediated signal transduction	1
cytoplasm organization	1
female gamete generation	1
axonogenesis	1
neuron projection guidance	1
cellular response to insulin stimulus	1
cellular response to fibroblast growth factor stimulus	1
Schwann cell differentiation	1
glial cell development	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
T cell differentiation in thymus	1
regulation of T cell differentiation	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
multicellular organismal process	1
developmental growth	1
Fc receptor signaling pathway	1

Protein interactions and networks

STRING

3254 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOS1	GRB2	P29354	999
SOS1	ABI1	Q8IZP0	997
SOS1	PTPN11	Q06124	997
SOS1	EPS8	Q12929	997
SOS1	SHC1	P29353	996
SOS1	RABIF	P47224	981
SOS1	HRAS	P01112	977
SOS1	KRAS	P01116	966
SOS1	VAV1	P15498	963
SOS1	FRS2	Q8WU20	962
SOS1	EGFR	P00533	943
SOS1	GAB2	Q9UQC2	922
SOS1	GRAP2	O75791	921
SOS1	SRC	P12931	910
SOS1	IRS1	P35568	903

IntAct

151 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
GRB2	SOS1	psi-mi:“MI:0915”(physical association)	0.970
SOS1	GRB2	psi-mi:“MI:0915”(physical association)	0.970
SOS1	GRB2	psi-mi:“MI:0407”(direct interaction)	0.970
GRB2	SOS1	psi-mi:“MI:0407”(direct interaction)	0.970
HRAS	SOS1	psi-mi:“MI:0407”(direct interaction)	0.940
SOS1	HRAS	psi-mi:“MI:0407”(direct interaction)	0.940

BioGRID (220): CSF1R (Affinity Capture-Western), SOS1 (Affinity Capture-MS), SOS1 (Affinity Capture-MS), SOS1 (Co-localization), SOS1 (Co-localization), SOS1 (Co-localization), SOS1 (Affinity Capture-Western), SOS1 (Synthetic Lethality), GRB2 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), EPS8 (Affinity Capture-Western), SOS1 (Affinity Capture-MS), SOS1 (Affinity Capture-Western), SOS1 (Affinity Capture-Western), PTPN11 (Affinity Capture-Western)

ESM2 similar proteins: A0JM95, A1A4S6, A2A2Y4, A4II46, A4IJ06, A6NI28, B2RQE8, B5DFQ4, F1LVW7, O60879, O60890, O70566, O95267, P0C7A6, P0CAX5, Q02384, Q07889, Q07890, Q08DP6, Q0P4Q4, Q28EC1, Q4V7P7, Q566W7, Q5R6F6, Q5R803, Q5U4T3, Q62245, Q69ZK0, Q6DBW1, Q6DHR3, Q6NTL4, Q6PCS4, Q6Y5D8, Q6ZM89, Q7YQL5, Q7YQL6, Q8AVG0, Q8BHD4, Q8IV61, Q8N9B8

Diamond homologs: A2AR50, A2CEA7, B0M0P8, B0UXH6, F1M386, F1MSG6, F1PBJ0, O14827, P27671, P28818, P70392, Q03385, Q03386, Q07889, Q07890, Q12967, Q13905, Q13972, Q3MIN7, Q3UYI5, Q4R7W3, Q54FF3, Q54PQ4, Q54TK8, Q552M5, Q55GH9, Q5JS13, Q5ZJK0, Q60695, Q86G47, Q86X27, Q8CHG7, Q8IS14, Q8IS15, Q8IS16, Q8IS18, Q8IS20, Q8IS21, Q8SSQ0, Q8SSW7

SIGNOR signaling

35 interactions.

A	Effect	B	Mechanism
SOS1	“up-regulates activity”	NRAS	“guanine nucleotide exchange factor”
SPRY1	down-regulates	SOS1	binding
SOS1	up-regulates	KRAS	“guanine nucleotide exchange factor”
“phosphatidic acid”	up-regulates	SOS1	“chemical activation”
MAPK1	“down-regulates activity”	SOS1	phosphorylation
GRB2	“up-regulates activity”	SOS1	relocalization
ERK1/2	“down-regulates activity”	SOS1	phosphorylation
ERK1/2	down-regulates	SOS1	phosphorylation
COPS3	“up-regulates quantity by stabilization”	SOS1	binding
MAPK3	down-regulates	SOS1	phosphorylation
Gbeta	down-regulates	SOS1	phosphorylation
SOS1	“up-regulates activity”	HRAS	“guanine nucleotide exchange factor”
PLCG1	up-regulates	SOS1	binding
SHC1	up-regulates	SOS1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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
Constitutive Signaling by EGFRvIII	7	96.1×	4e-11
Signaling by ERBB2 ECD mutants	7	90.4×	5e-11
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	7	76.9×	1e-10
Downstream signal transduction	10	73.2×	2e-14
GAB1 signalosome	6	73.2×	6e-09
Tie2 Signaling	5	57.8×	4e-07
Regulation of signaling by CBL	6	57.3×	2e-08
Signaling by ERBB2 KD Mutants	7	56.9×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	8	50.0×	1e-09
epidermal growth factor receptor signaling pathway	9	40.5×	6e-10
positive regulation of actin filament polymerization	5	30.0×	8e-05
insulin receptor signaling pathway	5	20.2×	3e-04
T cell receptor signaling pathway	5	13.8×	9e-04
regulation of cell shape	6	13.4×	3e-04
actin filament organization	6	12.9×	3e-04
neuron migration	5	12.2×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — SCLC.

Clinical variants and AI predictions

ClinVar

2126 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	38
Uncertain significance	1045
Likely benign	677
Benign	107

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
12869	NM_005633.4(SOS1):c.797C>A (p.Thr266Lys)	Pathogenic
12870	NM_005633.4(SOS1):c.806T>G (p.Met269Arg)	Pathogenic
12871	NM_005633.4(SOS1):c.1654A>G (p.Arg552Gly)	Pathogenic
12872	NM_005633.4(SOS1):c.1656G>C (p.Arg552Ser)	Pathogenic
12873	NM_005633.4(SOS1):c.1294T>C (p.Trp432Arg)	Pathogenic
1712183	NM_005633.4(SOS1):c.1294T>A (p.Trp432Arg)	Pathogenic
2059608	NM_005633.4(SOS1):c.2894C>G (p.Ala965Gly)	Pathogenic
2085827	NM_005633.4(SOS1):c.1394A>G (p.Asp465Gly)	Pathogenic
3247422	NC_000002.11:g.(?39212965)(39347563_?)dup	Pathogenic
3370396	SOS1, 4-BP INS, 3265TAAC	Pathogenic
3720319	NM_005633.4(SOS1):c.2186G>T (p.Trp729Leu)	Pathogenic
3777446	NM_005633.4(SOS1):c.807G>C (p.Met269Ile)	Pathogenic
40649	NM_005633.4(SOS1):c.322G>A (p.Glu108Lys)	Pathogenic
40651	NM_005633.4(SOS1):c.508A>G (p.Lys170Glu)	Pathogenic
40662	NM_005633.4(SOS1):c.806T>C (p.Met269Thr)	Pathogenic
40669	NM_005633.4(SOS1):c.1297G>A (p.Glu433Lys)	Pathogenic
40670	NM_005633.4(SOS1):c.1300G>C (p.Gly434Arg)	Pathogenic
40671	NM_005633.4(SOS1):c.1300_1301delinsAA (p.Gly434Lys)	Pathogenic
40673	NM_005633.4(SOS1):c.1322G>A (p.Cys441Tyr)	Pathogenic
40678	NM_005633.4(SOS1):c.1642A>C (p.Ser548Arg)	Pathogenic
40682	NM_005633.4(SOS1):c.1655G>C (p.Arg552Thr)	Pathogenic
40683	NM_005633.4(SOS1):c.1655G>A (p.Arg552Lys)	Pathogenic
40684	NM_005633.4(SOS1):c.1656G>T (p.Arg552Ser)	Pathogenic
40696	NM_005633.4(SOS1):c.2104T>C (p.Tyr702His)	Pathogenic
40706	NM_005633.4(SOS1):c.2536G>A (p.Glu846Lys)	Pathogenic
45379	NM_005633.4(SOS1):c.925G>T (p.Asp309Tyr)	Pathogenic
932923	NM_005633.4(SOS1):c.3134C>G (p.Pro1045Arg)	Pathogenic
1013410	NM_005633.4(SOS1):c.323A>T (p.Glu108Val)	Likely pathogenic
1066783	NM_005633.4(SOS1):c.1310T>A (p.Ile437Asn)	Likely pathogenic
1333569	NM_005633.4(SOS1):c.925G>A (p.Asp309Asn)	Likely pathogenic

SpliceAI

6412 predictions. Top by Δscore:

Variant	Effect	Δscore
2:38966000:TTCCA:T	acceptor_loss	1.0000
2:38966001:TCCAG:T	acceptor_loss	1.0000
2:38966002:CCA:C	acceptor_loss	1.0000
2:38966141:AAGAA:A	donor_gain	1.0000
2:38966142:AGAA:A	donor_gain	1.0000
2:38966143:GAA:G	donor_gain	1.0000
2:38966143:GAAG:G	donor_gain	1.0000
2:38966146:G:GG	donor_gain	1.0000
2:38987466:A:AC	donor_gain	1.0000
2:38987467:C:CC	donor_gain	1.0000
2:38987467:CTTTA:C	donor_gain	1.0000
2:38987468:TTTA:T	donor_loss	1.0000
2:38987469:TTA:T	donor_loss	1.0000
2:38987470:TACC:T	donor_loss	1.0000
2:38987568:T:C	acceptor_gain	1.0000
2:38996920:A:AC	donor_gain	1.0000
2:38996921:C:CC	donor_gain	1.0000
2:38996921:CAAAT:C	donor_gain	1.0000
2:38996925:T:C	donor_gain	1.0000
2:38997251:A:AC	donor_gain	1.0000
2:38997252:C:CC	donor_gain	1.0000
2:39006408:TTA:T	donor_loss	1.0000
2:39006409:TAC:T	donor_loss	1.0000
2:39006410:A:AC	donor_gain	1.0000
2:39006410:AC:A	donor_gain	1.0000
2:39006411:C:CT	donor_gain	1.0000
2:39006411:CC:C	donor_gain	1.0000
2:39006411:CCA:C	donor_gain	1.0000
2:39006411:CCAA:C	donor_gain	1.0000
2:39006411:CCAAA:C	donor_gain	1.0000

AlphaMissense

8792 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:38997282:A:C	Y979D	1.000
2:38997292:T:A	Q975H	1.000
2:38997292:T:G	Q975H	1.000
2:38997293:T:G	Q975P	1.000
2:38997297:A:C	Y974D	1.000
2:38997305:A:C	I971S	1.000
2:38997317:A:C	I967R	1.000
2:38997317:A:T	I967K	1.000
2:38997324:C:G	A965P	1.000
2:38997337:T:A	K960N	1.000
2:38997337:T:G	K960N	1.000
2:38997343:A:C	F958L	1.000
2:38997343:A:T	F958L	1.000
2:38997344:A:G	F958S	1.000
2:38997345:A:G	F958L	1.000
2:38997346:G:C	N957K	1.000
2:38997346:G:T	N957K	1.000
2:38997390:C:G	G943R	1.000
2:38997407:A:C	I937S	1.000
2:38997407:A:T	I937N	1.000
2:38997416:A:G	L934P	1.000
2:38997425:C:T	G931E	1.000
2:39006412:C:G	G931R	1.000
2:39006412:C:T	G931R	1.000
2:39006416:G:C	F929L	1.000
2:39006416:G:T	F929L	1.000
2:39006418:A:G	F929L	1.000
2:39006420:G:C	P928R	1.000
2:39006420:G:T	P928H	1.000
2:39006421:G:A	P928S	1.000

dbSNP variants (sampled 300 via entrez): RS1000023952 (2:39037087 G>A), RS1000051055 (2:39012515 C>A), RS1000069456 (2:39109546 C>T), RS1000082571 (2:39042615 G>C), RS1000084979 (2:39007398 G>C,T), RS1000085573 (2:39018945 G>A,C), RS1000115107 (2:39019135 A>G), RS1000118420 (2:39036918 G>T), RS1000140410 (2:39001320 C>A), RS1000151584 (2:39056608 A>G), RS1000161008 (2:39057703 C>A,T), RS1000206178 (2:39062441 A>AT), RS1000210290 (2:39099846 C>T), RS1000222263 (2:39124423 C>A,T), RS1000244203 (2:38984192 T>C)

Disease associations

OMIM: gene MIM:182530 | disease phenotypes: MIM:135300, MIM:610733, MIM:163950, MIM:601144, MIM:108800, MIM:114030, MIM:265500, MIM:609942, MIM:608629, MIM:192600

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome	Definitive	Autosomal dominant
Noonan syndrome 4	Definitive	Autosomal dominant
fibromatosis, gingival, 1	Strong	Autosomal dominant
hereditary gingival fibromatosis	Supportive	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant
cardiofaciocutaneous syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
Noonan syndrome	Definitive	AD
Costello syndrome	Disputed	AD
cardiofaciocutaneous syndrome	Disputed	AD

Mondo (25): RASopathy (MONDO:0021060), dilated cardiomyopathy (MONDO:0005021), fibromatosis, gingival, 1 (MONDO:0007609), Noonan syndrome 4 (MONDO:0012547), Noonan syndrome 1 (MONDO:0008104), Noonan syndrome (MONDO:0018997), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), 46,XY partial gonadal dysgenesis (MONDO:0016674), Brugada syndrome (MONDO:0015263), atrial septal defect (MONDO:0006664), cafe au lait spots, multiple (MONDO:0007245), intellectual disability (MONDO:0001071), obesity disorder (MONDO:0011122), ventricular tachycardia (MONDO:0005477), ptosis (MONDO:0000728)

Orphanet (21): RASopathy (Orphanet:536391), Dilated cardiomyopathy (Orphanet:217604), Hereditary gingival fibromatosis (Orphanet:2024), Noonan syndrome (Orphanet:648), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), 46,XY partial gonadal dysgenesis (Orphanet:251510), Brugada syndrome (Orphanet:130), Interatrial communication (Orphanet:1478), Familial isolated café-au-lait macules (Orphanet:2678), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Congenital pulmonary valvar stenosis (Orphanet:3189), Cystic hygroma (Orphanet:79486), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Rare cardiomyopathy (Orphanet:167848)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000073	Ureteral duplication
HP:0000078	Abnormality of the genital system
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000169	Gingival fibromatosis
HP:0000179	Thick lower lip vermilion
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
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:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002970_4	Corticobasal degeneration	3.000000e-06
GCST002971_4	Corticobasal degeneration	2.000000e-07
GCST009310_10	Sensorimotor dexterity	4.000000e-06
GCST010081_5	Aseptic loosening in total joint arthroplasty	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008354	cognitive function measurement
EFO:0010725	aseptic loosening

MeSH disease descriptors (18)

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
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
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
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D006344	Heart Septal Defects, Atrial	C14.240.400.560.375; C14.280.400.560.375; C16.131.240.400.560.375
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
C537421	Cafe au lait spots, multiple (supp.)
C535579	Cardiofaciocutaneous syndrome (supp.)
C536295	Joubert syndrome 3 (supp.)
C548082	Noonan Syndrome 4 (supp.)
C537846	Noonan like syndrome (supp.)
C537847	Noonan syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL2079846 (SINGLE PROTEIN), CHEMBL5169070 (PROTEIN-PROTEIN INTERACTION), CHEMBL5169077 (PROTEIN-PROTEIN INTERACTION), CHEMBL5291681 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465393 (PROTEIN COMPLEX), CHEMBL6193831 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 457,116 (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
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL53463	DOXORUBICIN	4	314,282
CHEMBL4535757	SOTORASIB	4	3,916
CHEMBL4594350	ADAGRASIB	4	2,814
CHEMBL5192659	MRTX-0902	1	39

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
HGF EXPRESSION	MET Tyrosine Kinase Inhibitor SGX523	Glioblastoma	Sensitivity/Response	CIViC D	EID1707

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Rho GEFs

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
MRTX0902	Binding	8.72	pKi
compound 37 [PMID: 36384290]	Binding	8.3	pIC50
BI-3406	Binding	8.01	pKi
BAY-293	Binding	7.68	pIC50
SOS1 PROTAC 9d	Agonist	7.36	pKd

Binding affinities (BindingDB)

515 measured of 752 human assays (794 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.47 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.52 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.55 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.56 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.56 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.59 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.64 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.66 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.68 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.68 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.69 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.69 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.76 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.76 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.77 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.81 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.82 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.86 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	0.87 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,95,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.99 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.99 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxylmethyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	1.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	1.2 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	1.2 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.4 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	1.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	1.6 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-5,6,12,16,19,33,36-heptamethyl-11-pentyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.7 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.7 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	2.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-12-ethyl-11-isobutyl-5,6,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	2.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-21-isobutyl-28-isopropyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	2.3 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isopentyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	2.4 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-(cyclopentylmethyl)-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	2.6 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	2.8 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-(4-chlorophenyl)ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	2.8 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
3-isopropyl-1,8-dimethyl-5-[[(1R)- 1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]amino]imidazo[4,5- g]phthalazin-2-one	IC50	2.82 nM	US-20250197407: TRICYCLIC PHTHALAZINES AND DERIVATIVES AS SOS1 INHIBITORS
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	3.6 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,12,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	3.6 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
3-tert-butyl-1,8-dimethyl-5-[[(1R)- 1-[3-(2-amino-1,1-difluoro-ethyl)- 2-fluoro- phenyl]ethyl]amino]imidazo[4,5- g]phthalazin-2-one	IC50	5.01 nM	US-20250197407: TRICYCLIC PHTHALAZINES AND DERIVATIVES AS SOS1 INHIBITORS
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isopentyl-5,12,16,19,33,36-hexamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-Undecaone	IC50	5.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
1-[(1S,4S)-5-[2-methyl-4-[[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]amino]pyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone	IC50	5.15 nM	US-20230357239: PYRIDO[2,3-D]PYRIMIDIN-4-AMINES AS SOS1 INHIBITORS
(5S,8S,11S,15S,1S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-35-(cyclohexylmethyl)-11-isobutyl-18-isopropyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4, 7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	5.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
1-cyclopropyl-3-methoxy-3,5- dimethyl-8-[[(1R)-1-[3-(1,1- difluoro-2-hydroxy-ethyl)-2- fluoro- phenyl]ethyl]amino]pyrrolo[2,3- g]phthalazin-2-one	IC50	5.75 nM	US-20250197407: TRICYCLIC PHTHALAZINES AND DERIVATIVES AS SOS1 INHIBITORS
US20250197424, Compound 23b	IC50	5.75 nM	US-20250197424: QUINOLINE COMPOUND AND USE THEREOF
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-35-(cyclohexylmethyl)-29-(3-fluoro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	6 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
1,8-dimethyl-3-(1- methylcyclopropyl)-5-[[(1R)-1-[3- (1,1-difluoro-2-hydroxy-ethyl)-2- methyl- phenyl]ethyl]amino]imidazo[4,5- g]phthalazin-2-one	IC50	6.03 nM	US-20250197407: TRICYCLIC PHTHALAZINES AND DERIVATIVES AS SOS1 INHIBITORS

ChEMBL bioactivities

1946 potent at pChembl≥5 of 2070 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL5845574
11.00	Ki	0.01	nM	CHEMBL5911560
11.00	Ki	0.01	nM	CHEMBL5866335
11.00	Ki	0.01	nM	CHEMBL5943213
11.00	Ki	0.01	nM	CHEMBL5892423
10.70	Ki	0.02	nM	CHEMBL6040455
10.30	Ki	0.05	nM	CHEMBL6029861
10.15	Ki	0.07	nM	CHEMBL5932934
10.10	Ki	0.08	nM	CHEMBL5793094
10.05	Ki	0.09	nM	CHEMBL5828147
9.96	Ki	0.11	nM	CHEMBL6009987
9.96	Ki	0.11	nM	CHEMBL5208088
9.96	Ki	0.11	nM	CHEMBL5902085
9.92	Ki	0.12	nM	CHEMBL5918654
9.77	Ki	0.17	nM	CHEMBL6026013
9.70	Ki	0.2	nM	CHEMBL5775957
9.70	Ki	0.2	nM	CHEMBL5952346
9.64	Ki	0.23	nM	CHEMBL6057619
9.62	Ki	0.24	nM	CHEMBL5202472
9.62	Ki	0.24	nM	CHEMBL6008647
9.60	Ki	0.25	nM	CHEMBL5839819
9.60	Ki	0.25	nM	CHEMBL5843562
9.60	Ki	0.25	nM	CHEMBL5932356
9.60	Ki	0.25	nM	CHEMBL5776229
9.60	Ki	0.25	nM	CHEMBL5873514
9.57	Ki	0.27	nM	CHEMBL5787966
9.55	Ki	0.28	nM	CHEMBL5888612
9.54	Ki	0.29	nM	CHEMBL5191446
9.54	Ki	0.29	nM	CHEMBL5846226
9.52	Ki	0.3	nM	CHEMBL5900677
9.51	Ki	0.31	nM	CHEMBL6015840
9.51	Ki	0.31	nM	CHEMBL5919408
9.49	Ki	0.32	nM	CHEMBL5940454
9.48	Ki	0.33	nM	CHEMBL5208088
9.48	Ki	0.33	nM	CHEMBL6001688
9.46	Ki	0.35	nM	CHEMBL6039021
9.44	Ki	0.36	nM	CHEMBL5202472
9.44	Kd	0.366	nM	CHEMBL5912092
9.44	Ki	0.36	nM	CHEMBL5971179
9.43	Ki	0.37	nM	CHEMBL5905726
9.41	Ki	0.39	nM	CHEMBL5814052
9.41	Ki	0.39	nM	CHEMBL5929210
9.40	Ki	0.4	nM	CHEMBL5931131
9.40	Ki	0.4	nM	CHEMBL6010320
9.40	Ki	0.4	nM	CHEMBL5772877
9.40	Ki	0.4	nM	CHEMBL5791611
9.39	Ki	0.41	nM	CHEMBL6018424
9.38	Ki	0.42	nM	CHEMBL6024286
9.38	Ki	0.42	nM	CHEMBL5980380
9.38	Ki	0.42	nM	CHEMBL6003162

PubChem BioAssay actives

561 with measured affinity, of 1726 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
4-methyl-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]-7-piperazin-1-ylphthalazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0003	uM
1-methyl-4-[1-methyl-4-[[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]amino]phthalazin-6-yl]piperazin-2-one	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0004	uM
4-methyl-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]-7-piperazin-1-ylpyrido[3,4-d]pyridazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0004	uM
6,7-dimethoxy-4-methyl-N-[(1R)-1-[4-[2-(methylaminomethyl)phenyl]thiophen-2-yl]ethyl]phthalazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0005	uM
4-methyl-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0009	uM
1-N,1-N-dimethyl-4-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]-6-piperazin-1-ylphthalazine-1,4-diamine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0011	uM
methyl (7R)-16-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-13-methyl-9-oxa-2,5,14,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaene-5-carboxylate	2142039: Inhibition of SOS1 (unknown origin) by HTRF assay	ic50	0.0011	uM
N-[(1R)-1-(3-bromo-2-methylphenyl)ethyl]-4-methyl-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0016	uM
2-methyl-3-[(1R)-1-[(4-methyl-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-yl)amino]ethyl]benzonitrile	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0019	uM
7-N,7-N,4-trimethyl-1-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]phthalazine-1,7-diamine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0022	uM
4-methyl-N-[(1R)-1-(2-methyl-3-methylsulfonylphenyl)ethyl]-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0023	uM
6,7-dimethoxy-4-methyl-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]phthalazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0026	uM
1-[(7R)-16-[[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl]amino]-14-methyl-9-oxa-2,5,13,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaen-5-yl]ethanone	1934785: Inhibition of human recombinant SOS1 (residue 564-1049)/KRAS G12C mutant protein-protein interaction at incubated for 25 degC for 60 mins by homogeneous time-resolved fluorescence (HTRF) method	ic50	0.0027	uM
N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine	1813975: Binding affinity to SOS1 (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0030	uM
N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-4-methyl-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0030	uM
4-methyl-N-[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]-7-piperidin-4-ylphthalazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0031	uM
1-[(3S)-3-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-7-methoxyquinolin-6-yl]oxypyrrolidin-1-yl]ethanone	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0038	uM
6,7-dimethoxy-N-[(1R)-1-[4-[2-(methylaminomethyl)phenyl]thiophen-2-yl]ethyl]phthalazin-1-amine	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0039	uM
1-[(7S)-17-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-15-methyl-10-oxa-2,5,14,16-tetrazatetracyclo[9.8.0.02,7.013,18]nonadeca-1(11),12,14,16,18-pentaene-5-carbonyl]cyclopropane-1-carbonitrile	1852453: Inhibition of N-terminal His6-tagged human recombinant SOS1(564 to 1049 residues)/human recombinant KRAS G12C mutant incubated for 60 mins by HTRF assay	ic50	0.0039	uM
1-[(7R)-16-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-14-methyl-9-oxa-2,5,13,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaen-5-yl]ethanone	1934785: Inhibition of human recombinant SOS1 (residue 564-1049)/KRAS G12C mutant protein-protein interaction at incubated for 25 degC for 60 mins by homogeneous time-resolved fluorescence (HTRF) method	ic50	0.0043	uM
1-[(7R)-16-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-14-methyl-9-oxa-2,5,13,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaene-5-carbonyl]cyclopropane-1-carbonitrile	2142035: Inhibition of SOS1 in human Calu-1 cells assessed as reduction in pERK level incubated for 24 hrs by HTRF analysis	ic50	0.0050	uM
5-[[(1R)-1-[3-(2-amino-1,1-difluoroethyl)-2-fluorophenyl]ethyl]amino]-3-tert-butyl-1,8-dimethylimidazo[4,5-g]phthalazin-2-one	2005766: Inhibition of N-terminal his 6-tagged human SOS1 (564 to 1049 residues)/ N-terminal GST tagged recombinant human wild type KRAS (1 to 188 residues) protein-protein interaction incubated for 60 mins by homogeneous time-resolved fluorescence assay	ic50	0.0050	uM
N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-1,7-naphthyridin-4-amine	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0052	uM
1-[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-1,7-naphthyridin-6-yl]piperazin-1-yl]ethanone	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0058	uM
(7R)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-14-methyl-5,9-dioxa-2,13,15-triazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaen-16-amine	1934785: Inhibition of human recombinant SOS1 (residue 564-1049)/KRAS G12C mutant protein-protein interaction at incubated for 25 degC for 60 mins by homogeneous time-resolved fluorescence (HTRF) method	ic50	0.0060	uM
N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-7-methoxy-6-[(3S)-pyrrolidin-3-yl]oxyquinolin-4-amine	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0060	uM
1-[(7R)-16-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-14-methyl-9-oxa-2,5,13,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaen-5-yl]ethanone	1934785: Inhibition of human recombinant SOS1 (residue 564-1049)/KRAS G12C mutant protein-protein interaction at incubated for 25 degC for 60 mins by homogeneous time-resolved fluorescence (HTRF) method	ic50	0.0063	uM
6,7-dimethoxy-2-methyl-N-[(1R)-1-[4-[2-(methylaminomethyl)phenyl]thiophen-2-yl]ethyl]quinazolin-4-amine	1954810: Inhibition of SOS1 (unknown origin)	ic50	0.0066	uM
N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-7-methoxy-6-[(3S)-oxolan-3-yl]oxyquinolin-4-amine	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0067	uM
4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-1,7-naphthyridin-6-yl]-1-methylpiperazin-2-one	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0069	uM
(4S)-2-amino-4-[3-[6-[(2S)-2,4-dimethylpiperazin-1-yl]-4-(4-prop-2-enoylpiperazin-1-yl)-2-pyridinyl]-1,2,4-oxadiazol-5-yl]-4-methyl-6,7-dihydro-5H-1-benzothiophene-3-carbonitrile	1918459: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction	ic50	0.0070	uM
N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-6-morpholin-4-yl-1,7-naphthyridin-4-amine	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0070	uM
(7R)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5,14-dimethyl-9-oxa-2,5,13,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaen-16-amine	1934785: Inhibition of human recombinant SOS1 (residue 564-1049)/KRAS G12C mutant protein-protein interaction at incubated for 25 degC for 60 mins by homogeneous time-resolved fluorescence (HTRF) method	ic50	0.0073	uM
3-cyclopropyl-5-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl]ethyl]amino]-1,8-dimethylimidazo[4,5-g]phthalazin-2-one	2005766: Inhibition of N-terminal his 6-tagged human SOS1 (564 to 1049 residues)/ N-terminal GST tagged recombinant human wild type KRAS (1 to 188 residues) protein-protein interaction incubated for 60 mins by homogeneous time-resolved fluorescence assay	ic50	0.0074	uM
5-[[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]amino]-1,8-dimethyl-3-propan-2-ylimidazo[4,5-g]phthalazin-2-one	2005766: Inhibition of N-terminal his 6-tagged human SOS1 (564 to 1049 residues)/ N-terminal GST tagged recombinant human wild type KRAS (1 to 188 residues) protein-protein interaction incubated for 60 mins by homogeneous time-resolved fluorescence assay	ic50	0.0076	uM
(2S,4R)-1-[(2S)-2-[[7-[4-[4-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-7-methoxy-2-methylquinazolin-6-yl]piperidin-1-yl]-7-oxoheptanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1948116: Binding affinity to GST-tagged human SOS1 (564 to 1049 residues) expressed in Escherichia coli BL21 (DE3) cells assessed as ternary complex formation by measuring dissociation constant incubated for 15 mins in the presence of 6His tagged human VCB by fluorescence polarization-based displacement assay	kd	0.0081	uM
5-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl]ethyl]amino]-1,8-dimethyl-3-propan-2-ylimidazo[4,5-g]phthalazin-2-one	2005766: Inhibition of N-terminal his 6-tagged human SOS1 (564 to 1049 residues)/ N-terminal GST tagged recombinant human wild type KRAS (1 to 188 residues) protein-protein interaction incubated for 60 mins by homogeneous time-resolved fluorescence assay	ic50	0.0085	uM
8-[[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl]amino]-3-ethyl-3-methoxy-1,5-dimethylpyrrolo[3,2-g]phthalazin-2-one	2005766: Inhibition of N-terminal his 6-tagged human SOS1 (564 to 1049 residues)/ N-terminal GST tagged recombinant human wild type KRAS (1 to 188 residues) protein-protein interaction incubated for 60 mins by homogeneous time-resolved fluorescence assay	ic50	0.0085	uM
1-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-1,7-naphthyridin-6-yl]piperidin-4-ol	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0085	uM
2-[[2-[5-[1-[(6,7-dimethoxyquinazolin-4-yl)amino]ethyl]thiophen-2-yl]phenyl]methylamino]ethanol	1954810: Inhibition of SOS1 (unknown origin)	ic50	0.0085	uM
N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-7-methoxyquinolin-4-amine	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0086	uM
1-[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-7-methoxyquinolin-6-yl]piperazin-1-yl]ethanone	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0088	uM
1-[16-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-14-methyl-9-oxa-2,5,13,15-tetrazatetracyclo[8.8.0.02,7.012,17]octadeca-1(10),11,13,15,17-pentaen-5-yl]ethanone	1934785: Inhibition of human recombinant SOS1 (residue 564-1049)/KRAS G12C mutant protein-protein interaction at incubated for 25 degC for 60 mins by homogeneous time-resolved fluorescence (HTRF) method	ic50	0.0088	uM
6-chloro-2-(2,6-diazaspiro[3.3]heptan-2-yl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)-1-[(4-fluoro-3,5-dimethylphenyl)methyl]benzimidazole	1387063: Binding affinity to human recombinant N-terminal His6-tagged SOS1 (564 to 1049 residues) expressed in BL21-RIL Escherichia coli by fluorescent probe S3 based fluorescence polarization anisotrophy saturation binding assay	kd	0.0090	uM
6-[(3R,4S)-3-fluoro-4-methoxypiperidin-1-yl]-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine	2021677: Inhibition of GST-tagged SOS1 (unknown origin) /His6-Tev tagged K-Ras G12D mutant (unknown origin) (1 to 169 residues) protein-protein interaction incubated for 30 mins by alphascreen assay	ic50	0.0090	uM
1-[4-[4-[[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-1,7-naphthyridin-6-yl]piperidin-1-yl]ethanone	2094842: Inhibition of SOS1/KRAS G12C mutant (unknown origin) protein-protein interaction incubated for 2 hrs by HTRF analysis	ic50	0.0097	uM
6,7-dimethoxy-N-[(1R)-1-phenylethyl]quinazolin-4-amine	2074611: Binding affinity to SOS1 (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0097	uM
8-[[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2,5-dimethylphenyl]ethyl]amino]-3-methoxy-1,3,5-trimethylpyrrolo[3,2-g]phthalazin-2-one	2005766: Inhibition of N-terminal his 6-tagged human SOS1 (564 to 1049 residues)/ N-terminal GST tagged recombinant human wild type KRAS (1 to 188 residues) protein-protein interaction incubated for 60 mins by homogeneous time-resolved fluorescence assay	ic50	0.0098	uM
6-chloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)-1-[(4-fluoro-3,5-dimethylphenyl)methyl]-2-piperazin-1-ylbenzimidazole	2074618: Binding affinity to SOS1 in human NCI-H358 cells expressing KRAS G12C mutant assessed as dissociation constant	kd	0.0100	uM
3-[(1R)-1-[(4-methyl-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-yl)amino]ethyl]benzonitrile	1893377: Binding affinity to N-terminal his-TEV-Avi-tagged human recombinant SOS1 expressed in Escherichia coli assessed as inhibition constant incubated for 10 to 15 mins by HTRF displacement assay	ki	0.0100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects expression	6
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation	5
Benzo(a)pyrene	affects methylation, increases expression	4
bisphenol A	decreases expression, increases expression, affects reaction, affects cotreatment, increases methylation	3
perfluorooctane sulfonic acid	decreases expression, affects expression, affects cotreatment	2
Cannabidiol	affects cotreatment, decreases expression	2
Doxorubicin	increases expression, decreases expression	2
Guanosine Diphosphate	increases reaction, decreases reaction, affects binding, decreases activity	2
Methylcholanthrene	increases expression, affects binding, increases reaction	2
Quercetin	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
moringin	affects cotreatment, decreases expression	1
BI-2852	affects binding, decreases reaction, decreases activity	1
allyl isothiocyanate	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tetrandrine	decreases expression	1
arsenite	decreases reaction, affects binding	1
butyraldehyde	decreases expression	1
bufalin	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
alpha-cobratoxin	decreases reaction, increases expression	1
benzo(e)pyrene	increases methylation	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
coumarin	decreases phosphorylation	1

ChEMBL screening assays

421 unique, capped per target: 409 binding, 12 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2089532	Binding	Inhibition to His6-tagged Sos1 catalytic domain-mediated nucleotide exchange by fluorimetric assay	Ras inhibition via direct Ras binding–is there a path forward? — Bioorg Med Chem Lett
CHEMBL5251884	Functional	In vivo induction of SOS1 degradation in human ASPC1 cells harboring KRAS G12D mutant xenografted BALB/c nude mouse assessed as decrease in SOS1 level at 50 mg/kg, ip administered twice daily for 3 weeks by Immunoblot analysis	Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers. — J Med Chem

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1CN	Abcam A-431 SOS1 KO	Cancer cell line	Female
CVCL_B8PV	Abcam HCT 116 SOS1 KO	Cancer cell line	Male
CVCL_B9BQ	Abcam MCF-7 SOS1 KO	Cancer cell line	Female
CVCL_B9SB	Abcam A-549 SOS1 KO	Cancer cell line	Male
CVCL_D8B9	Ubigene A-549 SOS1 KO	Cancer cell line	Male
CVCL_D8W0	Ubigene HCT 116 SOS1 KO	Cancer cell line	Male
CVCL_D9SQ	Ubigene HEK293 SOS1 KO	Transformed cell line	Female
CVCL_E0PP	Ubigene HeLa SOS1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT01536717	PHASE4	SUSPENDED	Comparison of the Local Anaesthetics Articaine and Bupivacaine in Treatment of Acute Sternum Pain After Heart Surgery
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT06631534	PHASE4	RECRUITING	Effect of Dexmedetomidine Supplementation to General Anaesthesia in Paediatric Transcatheter Closure of Atrial Septal Defect
NCT07054541	PHASE4	NOT_YET_RECRUITING	A Novel Echocardiography-Guided Strategy for Percutateous Closure of Atrial Septal Defect Assisted by PannaWire
NCT07226739	PHASE4	NOT_YET_RECRUITING	Comprehensive Toileting Program
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
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT00480740	PHASE3	COMPLETED	The Pharmacology and Hemodynamics of Dexmedetomidine in Children With Congenital Heart Disease
NCT01773252	PHASE3	TERMINATED	Right to Left Cardiac Shunt Detection
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
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
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	PHASE2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery