Abstract LB163: Discovery and characterization of QTX3544, a potent, selective, and orally bioavailable allosteric G12V preferring multi KRAS inhibitor

Abstract Oncogenic KRAS mutations occur in approximately 25% of all human cancers with KRAS G12V being one of the most frequently occurring variants, particularly in pancreatic, colorectal, and lung cancers. These oncogenic mutations cause sustained activation of the mitogen activated protein kinase (MAPK) pathway, which ultimately drives tumorigenesis. While newly approved covalent inhibitors to KRASG12C have demonstrated clinical benefit to patients harboring this mutation, there are no approved drugs targeting mutations beyond KRASG12C, highlighting a significant clinical need. Here we show that QTX3544 is a potent and orally bioavailable KRASG12V preferring multi KRAS inhibitor. QTX3544 exhibited picomolar binding affinity (0. 08 nM) and SOS mediated nucleotide inhibition (0. 07 nM) to the inactive form of KRASG12V. Furthermore, QTX3544 inhibited “on state” KRAS activity in both biochemical and cellular assays. In vitro, QTX3544 significantly inhibited downstream ERK phosphorylation and cell proliferation in KRASG12V driven cancer cell lines. Similar inhibitory effects were observed across additional mutant KRAS cancer cell lines, including KRAS G12A, KRAS G13D, and KRAS Q61H, among others. Notably, QTX3544 displayed no impact against HRAS, NRAS or BRAF mutant cells. In vivo, oral administration of QTX3544 achieved sustained systemic exposure required for efficacy, indicating potential durable inhibition of KRAS signaling. QTX3544 demonstrated dose dependent anti tumor efficacy and significant tumor regression in various KRASG12V driven xenograft models when administered orally twice daily (BID). The physiochemical profile of QTX3544 is favorable with good measured LogD, solubility, and permeability. QTX3544 exhibits weak Cytochrome P450 inhibition (direct and time dependent) with a favorable in vitro off target selectivity/safety profile. The systemic clearance in rats and dogs was moderate to high, respectively, with good oral bioavailability. QTX3544 was generally well tolerated in rat and dog repeat dose tolerability studies. In addition, QTX3544 showed good brain penetration in mice. Taken together, this preclinical characterization supports the advancement of QTX3544 into IND enabling studies for KRAS G12V mutant cancers. Citation Format: Yang W. Zhang, Elizabeth Donohue Vo, Pei Gan, Dave Rominger, Jillian M. Silva, Yang J. Zhang, Christopher Pan, Greg Lee, John M. Micozzi, Ben Reid, Brooke McDonough, Arghyotri Sinha, Audrey Hospital, Doug Krauth, Juan I. Luengo, Mike Kramer, Cameron Pitt, Hong Lin. Discovery and characterization of QTX3544, a potent, selective, and orally bioavailable allosteric G12V preferring multi KRAS inhibitor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB163.