Abstract ND01: AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors

Abstract KRAS is one of the most frequently mutated oncogenes in human cancer (present in ∼25% of cancers). Recent approvals of covalent KRAS G12C inhibitors (KRAS G12Ci) have demonstrated that this once “undruggable” target can now be inhibited with small-molecule allosteric inhibitors to deliver meaningful clinical benefit. Approved inhibitors (sotorasib & adagrasib) are only effective for tumors harboring the KRAS G12C mutation, however, and major unmet need remains for the larger population of patients (∼140k patients/year, USA) that bear other oncogenic KRAS mutations (e.g., KRAS G12D, G12V, etc.). Leveraging insights from KRAS G12Ci, we here report the structure- and property-based design of a non-covalent “pan-KRAS” inhibitor, AMG 410, which binds to the most clinically relevant KRAS mutants (e.g., G12D, G12V, G13D; IC50 values = 1-4 nM) via the same allosteric pocket employed by approved KRAS G12C inhibitors. AMG 410 shows potent antiproliferative activity in KRAS-mutant cells (median IC50 = 12 nM). Importantly, AMG 410 is highly specific for KRAS, demonstrating greater than 100-fold selectivity against both HRAS and NRAS, differentiating AMG 410 from pan-RAS inhibitors through its ability to avoid anti-proliferative effects in non-KRAS-transformed cells (median IC50 >5 µM). In contrast to “on”-state-only inhibitors, AMG 410 is a dual GTP(on)- and GDP(off)-state inhibitor (KD(GDP-state) = 1 nM; KD(GTP-state) = 22 nM), enabling blockade of KRAS signaling in a cycling state-independent manner, while also allowing AMG 410 to block proliferation in wildtype KRAS-amplified tumor cells. AMG 410 demonstrates strong pre-clinical efficacy, robustly lowing phosphorylated ERK levels throughout dosing cycles and achieving tumor stasis or regression across a broad set of colorectal, pancreatic, and lung cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring a diverse set of KRAS mutant alleles including G12D, G12V, G12C, & G13D. AMG 410 also shows enhanced in vivo efficacy in combination with other targeted therapies or immunotherapy and good pre-clinical tolerability, highlighting the potential of an HRAS- and NRAS-sparing pan-KRAS inhibitor to show improved efficacy and clinical tolerability in the combination setting. Based on a promising non-clinical safety and efficacy profile, a first-in-human study with AMG 410 in a range of solid tumor indications (CRC, PDAC, NSCLC) is planned. Citation Format: Brian A. Lanman, Ryan P. Wurz, Rati Verma, Tao Osgood, Kevin Gaida, Deanna Mohn, Ying-Chu Chen, Gilbert Diaz, Anne Y. Saiki, Paul E. Hughes, Christopher Mohr, Amit Vaish, Yanyan Tudor, Upendra P. Dahal, Prashant Agarwal, Christine Mollica. AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors [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 ND01.