SOS1 Inhibitor Screening Library | Targeted and Focused Screening Libraries | Screening Libraries

SOS1 (Son of Sevenless 1) is a critical guanine nucleotide exchange factor (GEF) that activates RAS proteins within the RAS-MAPK signaling pathway, a pivotal cascade regulating cellular proliferation, differentiation, and survival [1]. Aberrant activation of the RAS-MAPK cascade is implicated in multiple cancers, including pancreatic adenocarcinoma, non-small cell lung cancer (NSCLC), and juvenile myelomonocytic leukemia, making SOS1 a strategically important and therapeutically tractable target [2,3]. Disruption of the SOS1–KRAS protein–protein interaction (PPI) represents a validated approach to suppress oncogenic RAS signaling [4].

Our cheminformatics team has prepared a specialized screening set of predicted small-molecule SOS1 inhibitors.

Key Features

2,600 drug-like compounds
Target: SOS1 (RAS pathway modulation)
Focus on SOS1-KRAS PPI disruption
Structure-based design and docking refinement
Filtered for drug-likeness and medicinal chemistry suitability
Applicable to oncology-focused hit discovery

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

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Representative screening compounds from the Screening Library

Scientific rationale

Direct targeting of mutant RAS proteins has historically been challenging, earning them the designation “undruggable” due to high GTP affinity and limited druggable binding pockets [5]. Recent structural and biochemical advances have identified SOS1 as a tractable upstream target, with small molecules capable of binding defined pockets at the SOS1–KRAS interface [6]. Such inhibitors can attenuate RAS activation by stabilizing inactive SOS1 conformations or disrupting SOS1–KRAS complex formation, thereby blocking downstream oncogenic signaling [7-8].

SOS1 gain-of-function variants in the Ras-MAPK pathway [DOI: 10.1038/s41398-023-02504-4, 10.1159/000201106]

Fig. 1. SOS1 gain-of-function variants in the Ras-MAPK pathway [DOI: 10.1038/s41398-023-02504-4, 10.1159/000201106]

Compound selection strategy

This screening set was developed by structure-based virtual screening using the crystal structure of SOS1 (PDB ID: 8XJJ). Protein preparation included optimization of protonation states, correction of side chains, and binding site validation.

A reference set of known SOS1 inhibitors was used to benchmark docking performance. High-throughput virtual screening (HTVS) was followed by extra-precision docking to refine binding affinity predictions. Final compound selection incorporated:

In-house drug-likeness filters
PAINS and structural liability filters
Removal of chemically undesirable or non-drug-like chemotypes

The resulting screening library features more than 2,600 chemically diverse, synthetically accessible molecules with high SOS1 binding potential, reduced assay interference risk, and suitability for downstream medicinal chemistry optimization.

Verification of protein structure and surface during test docking.

Fig. 2. Verification of protein structure and surface during test docking.

Compound F6677-1629 in the binding site of the SOS1 protein. The complex was obtained using molecular docking.

Fig. 3. Compound F6677-1629 in the binding site of the SOS1 protein. The complex was obtained using molecular docking.

Reference:

Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011 Mar;2(3):344-58. doi: 10.1177/1947601911411084. PMID: 21779504; PMCID: PMC3128640.
Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J, Badock V, Mastouri J, Petersen K, Siemeister G, Kahmann JD, Wegener D, Böhnke N, Eis K, Graham K, Wortmann L, von Nussbaum F, Bader B. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. doi: 10.1073/pnas.1812963116. Epub 2019 Jan 25. PMID: 30683722; PMCID: PMC6377443.
Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017 Jun 29;170(1):17-33. doi: 10.1016/j.cell.2017.06.009. PMID: 28666118; PMCID: PMC5555610.
Mustachio LM, Chelariu-Raicu A, Szekvolgyi L, Roszik J. Targeting KRAS in Cancer: Promising Therapeutic Strategies. Cancers (Basel). 2021 Mar 10;13(6):1204. doi: 10.3390/cancers13061204. PMID: 33801965; PMCID: PMC7999304.
Papke B, Der CJ. Drugging RAS: Know the enemy. Science. 2017 Mar 17;355(6330):1158-1163. doi: 10.1126/science.aam7622. Epub 2017 Mar 16. PMID: 28302824.
Evelyn CR, Duan X, Biesiada J, Seibel WL, Meller J, Zheng Y. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1. Chem Biol. 2014 Dec 18;21(12):1618-28. doi: 10.1016/j.chembiol.2014.09.018. Epub 2014 Nov 20. PMID: 25455859; PMCID: PMC4272618.
Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020 Aug;19(8):533-552. doi: 10.1038/s41573-020-0068-6. Epub 2020 Jun 11. Erratum in: Nat Rev Drug Discov. 2020 Dec;19(12):902. doi: 10.1038/s41573-020-0089-1. PMID: 32528145; PMCID: PMC7809886.
Burns MC, Sun Q, Daniels RN, Camper D, Kennedy JP, Phan J, Olejniczak ET, Lee T, Waterson AG, Rossanese OW, Fesik SW. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3401-6. doi: 10.1073/pnas.1315798111. Epub 2014 Feb 18. PMID: 24550516; PMCID: PMC3948241.