Abstract 5900: INCB161734: A novel, potent, and orally bioavailable KRAS G12D selective inhibitor demonstrates antitumor activity in KRAS G12D mutant tumors

作者：Matthew R. Farren, Valerie Roman, Alexandra Gallion, Abdellah Allali‐Hassani, Alexander Sokolsky, Weixi Kong, Amanda Smith, Hui Wang, Gina Correa, Marc C. Deller, L.B. Epling, Jessica Procak, Guofeng Zhang, Katherine Pecko, Keith Kennedy, Jason Boer, Kerri Kurzeja-Lipinski, Maryanne Covington, Kwang-Jong Chen, Renee Wallower, Jennifer Rocha, Rina Pan, Anthony Perry, Brad Yuska, Xiaozhao Wang, Ricardo Macarron, Sunkyu Kim · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/1538-7445.am2024-5900 · 被引用次数：14 · 研究领域：Ubiquitin and proteasome pathways、Protein Kinase Regulation and GTPase Signaling、Cancer, Hypoxia, and Metabolism

Abstract KRAS G12D (G12D) is one of the most frequent oncogenic driver mutations, and is especially common in pancreatic (PDAC) and colorectal (CRC) cancers. Patients with G12D-mutated disease experience poor treatment outcomes, representing a significant unmet medical need. G12D mutation results in constitutively active signaling, including hyperactivation of the ERK and PI3K pathways, which drive cell proliferation and survival. Here we describe INCB161734, a novel, potent, selective, and orally bioavailable small molecule G12D inhibitor that demonstrates in vivo efficacy in G12D-bearing tumor models. INCB161734 binds to both the GDP and GTP forms of the G12D mutant at the switch II pocket with picomolar affinity (KD), and exhibits >80-fold selectivity over wildtype (WT) KRAS. INCB161734 potently inhibits SOS1-dependent GDP/GTP exchange activity in cell-free assays (IC50 <3 nM), and exhibits >40-fold selectivity for G12D versus WT KRAS. Additionally, INCB161734 demonstrates high selectivity for G12D over WT in various cellular assays using G12D mutant versus WT cancer derived cell lines. INCB161734 potently inhibits ERK phosphorylation (a correlate for KRAS activity), with a mean IC50 of 14.3 nM (range: 1.9-45.2 nM) across 7 human and 3 mouse G12D cell lines; mean 21.5% inhibition was observed at 1 μM (maximum tested concentration) across 14 WT cell lines. Likewise, INCB161734 inhibits proliferation of G12D mutant cell lines, with a mean IC50 of 154 nM ...