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SOS Ras/Rac guanine nucleotide exchange factor 1

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Target not currently curated in GtoImmuPdb

Target id: 3096

Nomenclature: SOS Ras/Rac guanine nucleotide exchange factor 1

Family: Rho GEFs

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1333 2p22.1 SOS1 SOS Ras/Rac guanine nucleotide exchange factor 1
Mouse - 1319 17 50.67 cM Sos1 SOS Ras/Rac guanine nucleotide exchange factor 1
Rat - 1319 6q11 Sos1 SOS Ras/Rac guanine nucleotide exchange factor 1
Previous and Unofficial Names Click here for help
GF1 | gingival fibromatosis, hereditary, 1 (GINGF) | HGF | son of sevenless homolog 1 (Drosophila) | SOS-1
Database Links Click here for help
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Ras guanine nucleotide exchange factor SOS1 (Rem-cdc25) in complex with small molecule inhibitor BAY-293 (compound 23)
PDB Id:  5OVI
Ligand:  BAY-293
Resolution:  2.2Å
Species:  Human
References:  2

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SOS1 PROTAC 9d Small molecule or natural product Hs Agonist 7.4 pKd 3
pKd 7.4 (Kd 4.4x10-8 M) [3]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MRTX0902 Small molecule or natural product Ligand has a PDB structure Hs Binding 8.7 pKi 5
pKi 8.7 (Ki 1.9x10-9 M) [5]
BI-3406 Small molecule or natural product Ligand has a PDB structure Hs Binding 8.0 pKi 4
pKi 8.0 (Ki 9.7x10-9 M) [4]
Description: Binding affinity determined by SPR
compound 37 [PMID: 36384290] Small molecule or natural product Hs Binding 8.3 pIC50 8
pIC50 8.3 (IC50 5x10-9 M) [8]
Description: Inhibition of ERK phosphorylation in DLD-1 cells
BAY-293 Small molecule or natural product Ligand has a PDB structure Hs Binding 7.7 pIC50 2
pIC50 7.7 (IC50 2.1x10-8 M) [2]
Description: Binding to SOS1 in vitro.
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cytokine production & signalling
Immuno Process:  Immune system development
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
General Comments
SOS1 is a guanine nucleotide exchange factor that regulates the activation state of RAS GTPases. When the RAS/SOS1 complex forms RAS can reload with GTP and is activated. Inhibition of RAS/SOS1 formation prevents reloading with GTP and blocks RAS pathway activation.

Blocking the RAS/SOS1 interaction using small-molecules is being explored as a novel antiproliferative mechanism for cancer therapy [1-2,6-7]. This mechanism is operational irrespective of the KRAS alleles present in targeted tumours (including the most common G12D/V/C and G13D oncoproteins).

References

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1. Burns MC, Howes JE, Sun Q, Little AJ, Camper DV, Abbott JR, Phan J, Lee T, Waterson AG, Rossanese OW et al.. (2018) High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling. Anal Biochem, 548: 44-52. [PMID:29444450]

2. Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J et al.. (2019) Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci USA, 116 (7): 2551-2560. [PMID:30683722]

3. Hodges TR, Abbott JR, Little AJ, Sarkar D, Salovich JM, Howes JE, Akan DT, Sai J, Arnold AL, Browning C et al.. (2018) Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS. J Med Chem, 61 (19): 8875-8894. [PMID:30205005]

4. Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, Sanderson MP, Kessler D, Trapani F, Arnhof H et al.. (2021) BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discov, 11 (1): 142-157. [PMID:32816843]

5. Ketcham JM, Haling J, Khare S, Bowcut V, Briere DM, Burns AC, Gunn RJ, Ivetac A, Kuehler J, Kulyk S et al.. (2022) Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction. J Med Chem, 65 (14): 9678-9690. [PMID:35833726]

6. Lu S, Jang H, Zhang J, Nussinov R. (2016) Inhibitors of Ras-SOS Interactions. ChemMedChem, 11 (8): 814-21. [PMID:26630662]

7. Winter JJ, Anderson M, Blades K, Brassington C, Breeze AL, Chresta C, Embrey K, Fairley G, Faulder P, Finlay MR et al.. (2015) Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J Med Chem, 58 (5): 2265-74. [PMID:25695162]

8. Zhang S, Zhang Y, Chen X, Xu J, Fang H, Li Y, Liu Y, He H. (2022) Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma. J Med Chem, 65 (23): 15856-15877. [PMID:36384290]

How to cite this page

Rho GEFs: SOS Ras/Rac guanine nucleotide exchange factor 1. Last modified on 21/11/2022. Accessed on 19/06/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3096.