Abstract 418: ETX-929, a potential best-In-class, oral, highly potent and selective dual ON/OFF state Pan-KRAS small molecule inhibitor for the treatment of KRAS mutant and wild-type amplified cancers.

Abstract Oncogenic KRAS alterations occur in approximately 23% of all human cancers. The most common oncogenic KRAS alterations are G12D (∼31%), G12V (∼24%), and G12C (∼15%) mutations. In addition, ∼10% of KRAS-altered cancers have wild-type (WT) KRAS amplification or harbor multiple oncogenic KRAS alterations, including co-occurring KRAS mutations and amplifications. While there have been drug approvals for KRASG12C targeting covalent inhibitors, there are currently no approved targeted therapies against other oncogenic KRAS alterations. Pan-KRAS inhibitors that target multiple oncogenic KRAS alterations while sparing other RAS isoforms have the potential to treat broad patient populations and address resistance to mutant selective KRAS inhibition while avoiding the on-target toxicities associated with pan-RAS inhibition. ETX-929 is an orally bioavailable, potent, dual GTP (ON)- and GDP (OFF)-state pan-KRAS inhibitor with excellent selectivity over other RAS isoforms. ETX-929 binds WT and mutant KRAS in active (ON) and inactive (OFF) conformations with high affinity KD(ON-state) = single digit nanomolar; KD(OFF-state) = picomolar and 100-fold selectivity over NRAS and HRAS. In the KRAS-RAF1 RAS-binding domain biochemical assay, ETX-929 potently inhibited complex formation when KRAS (WT / mutant) was either in the active GMPPNP-bound state (single digit nM IC50) or inactive GDP-bound state (pM IC50). In cells, ETX-929’s dual ON / OFF-state inhibitory activity potently inhibits KRAS mutants that rapidly cycle between GTP- and GDP-bound states (KRASWTamp, KRASG12C) as well as slow cycling mutants (KRASG12V and KRASQ61H) that predominantly reside in the ON state. In a broad panel of KRAS mutant (G12X, G13D, Q61H) and WT amplified cancer cell lines, ETX-929 potently inhibited the KRAS pathway (pERK median IC50 = 0.9 nM) and cell proliferation (median IC50 = 6.23 nM), while showing no viability effects on low copy number WT KRAS or mutant NRAS / HRAS cells. Oral ETX-929 showed dose-dependent exposures with concordant sustained tumor pERK reductions, inducing tumor stasis or regression in colorectal, stomach, and lung cancer cell line-derived xenograft models harboring KRAS alterations (G12D, G12V, G12C, and WT amplified). ETX-929 also shows good cross-species pharmacokinetics including higher species, excellent pre-clinical tolerability, and no meaningful off-target activity or in vitro safety signals, supporting its advancement toward clinical development. Overall, ETX-929 is a potential best-in-class, pan-KRAS inhibitor with superior potency, selectivity over NRAS / HRAS, excellent efficacy and favorable drug-like properties that could improve outcomes for KRAS-driven cancers that currently lack targeted therapeutic options. Citation Format: Meghana M. Kulkarni, Lei Cui, Hongbo Deng, Tao Liu, Jingyan Gao, Fei Peng, Ying Lin, Yong Tang, Karan Kapoor, Minghong Hao, Robert F. Koncar, Robbie Chen, Eric Simone, Raj Nagaraja, Shengfang Jin, Jeffery Kutok. ETX-929, a potential best-In-class, oral, highly potent and selective dual ON / OFF state Pan-KRAS small molecule inhibitor for the treatment of KRAS mutant and wild-type amplified cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 418.