Abstract LB429: Discovery of a novel SOS1-KRASmulti inhibitor, HM101207, demonstrates a broad-spectrum antitumor activity across KRAS-MAPK mutant cancers

Abstract The RAS subfamily is a well-known oncogene with the highest mutation rate and poor prognosis among various cancers. Among the RAS subfamily, KRAS is the most frequent mutation isoform, especially with a prevalence of approximately 35%∼90% in NSCLC, CRC, and PDAC. KRAS protein cycles between "off" (inactive) and "on" (active) states induce downstream signal transduction to promote cell proliferation and survival. Son of sevenless homolog 1 (SOS1) is one of guanine nucleotide exchange factor (GEF) responsible for a binary molecular switch to activate KRAS as well as a node in the negative feedback loop in the RTK-KRAS-MAPK signaling pathway. Targeting SOS1-KRAS interaction has the potential to modulate the GDP-bound state of pan-KRAS, enabling to suppress the various KRAS-driven cancers. Herein, we introduce HM101207, SOS1-KRASmulti inhibitor with a novel scaffold and favorable DMPK profiles for KRAS regulation and suggest its suitable druggability. We developed HM101207, an orally administered SOS1 inhibitor that blocks GTP binding to KRAS and investigated the profiles and mechanistic studies of drug efficacy through in vitro and in vivo models. HM101207 exhibited the wide spectrum inhibitory potency including p-ERK inhibition across KRAS mutants. HM101207 inhibited SOS1-mediated GTP exchange on KRAS WT, G12C/D/S/V/R, and Q61H mutations and decreased ERK phosphorylation in KRAS G12C-mutant cancer cell lines. Through a three-dimensional (3D) spheroid growth inhibition assay, HM101207 demonstrated promising GI50 against KRAS G12C-mutant as well as PTPN11 or NF1-mutant cancer cell lines. In vitro studies with human liver microsomes showed that HM101207 did not inhibit directly major CYP enzymes, also did not a time-dependent inhibitor (TDI). We expected the risk of drug-drug interaction (DDI) to be low potential of HM101207 with co-administered drugs. A low plasma protein binding rate suggests a higher unbound drug concentration. Furthermore, HM101207 showed promising antitumor efficacy in KRAS mutation xenograft model in dose dependent manner. Additionally, the combination of HM101207 with KRAS-MAPK vertical pathway such as KRAS G12C or MEK inhibitors led the powerful synergistic activity without significant body weight loss or notable clinical observations. Based on our exploratory research, HM101207 could be suggested as a promising therapeutic candidate for diverse cancers causing by the hyperactivation of oncogenic KRAS signaling. Preclinical studies have shown that HM101207 may overcome existing limitations of KRAS G12C or MEK inhibitors through combination strategy. HM101207 is currently preparing in IND enabling GLP-toxicity studies to support further clinical development. Citation Format: Jaeyul Choi, Wongi Park, Soye Jeon, Heesun Moon, Yunju Kang, Eun Young Lee, Seung Hyun Jung, Jooyun Byun, Sang Hyun Lee, Young Gil Ahn. Discovery of a novel SOS1-KRASmulti inhibitor, HM101207, demonstrates a broad-spectrum antitumor activity across KRAS-MAPK mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB429.