Son of Sevenless homolog 1–Kirsten rat sarcoma virus oncogene homolog interaction (SOS1–KRAS interaction)

The Son of Sevenless homolog 1 (SOS1)–Kirsten rat sarcoma virus oncogene homolog (KRAS) interaction is a fundamental regulatory mechanism in the Ras/MAPK signaling pathway [1, 2]. SOS1 acts as a guanine nucleotide exchange factor (GEF) that catalyzes the release of GDP from KRAS, allowing GTP to bind and activate the protein for downstream signaling [1, 3]. In many cancers, KRAS is constitutively active due to mutations, driving uncontrolled cell proliferation and survival [2]. Targeting the SOS1–pan-KRAS interaction offers a strategy to inhibit multiple KRAS variants, including G12D, G12V, and G13D, by preventing their activation regardless of the specific mutation [3, 4]. Small molecule inhibitors designed for this target bind to SOS1 and disrupt its ability to form a functional complex with KRAS, effectively keeping the GTPase in its 'off' state [3, 5]. This approach is particularly valuable as it can potentially overcome the limitations of allele-specific inhibitors and address a wider patient population across various KRAS-driven malignancies [4]. Clinical trials are currently evaluating these inhibitors both as monotherapies and in combination with other MAPK pathway blockers to improve efficacy and delay the onset of resistance [4, 5]. Sources: [1] UniProt Consortium. SOS1 (Q07889) and KRAS (P01116). [2] National Cancer Institute (NCI). RAS Mutations in Cancer. [3] Hofmann, M. H., et al. (2021). BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective Across a Broad Range of KRAS-Mutated Cancers. Cancer Discovery. [4] ClinicalTrials.gov. Study of BI 1701963 in Patients With Solid Tumors Harboring KRAS Mutations (NCT04111458). [5] Hillig, R. C., et al. (2019). Discovery of potent SOS1 inhibitors that block RAS activation of wild-type and mutant RAS. PNAS.

Other names

SOS1-KRAS complexSOS1-pan-KRASSOS1-Ras interactionSOS1-mediated KRAS activation

Small molecule inhibitors bind to the catalytic site or an allosteric pocket of SOS1 to disrupt its physical interaction with KRAS, thereby preventing the exchange of GDP for GTP and maintaining KRAS in its inactive state to suppress downstream MAPK signaling.