Abstract 1625: A novel SOS1 inhibitor, HM99462 demonstrates antitumor activity against KRAS-mutant cancers

Abstract KRAS is a well-known oncogene with the highest mutation rate among various cancers. KRAS cycles between GDP-loaded ‘off’ and GTP-loaded ‘on’ states induce downstream signal transduction to promote cell proliferation and survival. Interconversion between ‘on’ and ‘off’ states is assisted by SOS (Son of sevenless), a binary molecular switch of KRAS. SOS family as a guanine-nucleotide exchange factor (GEF) is composed of SOS1 and SOS2, but SOS1 is a node in the negative feedback regulation of the KRAS pathway while SOS2 is not. Since SOS1 is a direct upstream of KRAS, SOS1 inhibitor has the potential to be a pan-KRAS inhibitor affecting various cancers harboring diverse KRAS mutations. Here, we suggest HM99462 as a novel SOS1 inhibitor for KRAS regulation and present its promising druggability. We developed HM99462 for an orally bioavailable SOS1 inhibitor which abrogates GTP-binding to KRAS and the profile of drug potency and mechanism of action was examined with in vitro and in vivo models. Biochemical activity on SOS1 was evaluated by a GTP-exchange assay on KRAS G12C, D, and V, and HM99462 showed excellent inhibitory activity, while SOS2 action was not affected. Moreover, HM99462 decreased ERK phosphorylation in various cancer cell lines harboring different major KRAS mutation statuses such as KRAS G12C, G12V, G12D, or G13D. Growth inhibition assay was performed using a three-dimensional (3D) conformation culture that mimics the complexity and heterogeneity of tumors and has elevated p-ERK. In this 3D spheroid growth inhibition assay, HM99462 demonstrated significantly effective GI50 against various KRAS mutant cell lines. HM99462 also had almost no inhibition of seven CYP isozymes guided by the FDA, and a low plasma protein binding rate around 80%, offering high unbound drug concentration. Additionally, HM99462 was evaluated in cancer cell xenograft mouse models harboring various KRAS mutations. Reasonable tumor growth inhibition activity was shown within tolerable doses when administered alone. Also, the combination of HM99462 with KRAS G12C or MEK inhibitors led to synergistic anti-tumor activity in both in vitro and in vivo models with several KRAS mutations. Through our exploratory study, a novel SOS1 inhibitor, HM99462 could be suggested as an appropriate therapeutic agent for diverse inhibitory activity against cancers causing by the hyperactivation of oncogenic KRAS signaling. And it has the potential to overcome the limitations of KRAS G12C or MEK inhibitor through combination. HM99462 is currently in IND enabling GLP-toxicity studies, planned to initiate clinical study in early 2024. Citation Format: Seung Hyun Jung, Jaeyul Choi, Wongi Park, Jooyun Byun, Semi Lim, Youngjoo Lee, Yu-Yon Kim, Hyunjin Park, So-Ye Jeon, Taehun Song, Kyungjin Choi, Tae-yeon Kong, Heecheol Kim, Wook Jang, EunYoung Lee, Minhwa Kim, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. A novel SOS1 inhibitor, HM99462 demonstrates antitumor activity against KRAS-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1625.