Abstract 2627: The small molecule KRAS inhibitor, TEB-17231, blocks tumor progression and overcomes KRASG12C inhibitor mediated resistance
Authors: Xu Zusheng , Weaver David T. , Drakas Robert , Lou Yangtong 
Published: April 2023

KRAS pathways are frequently upregulated in cancers bearing KRAS mutations or by other signaling modifications. Also, resistance to KRASG12C inhibitors and other KRAS/RAF/MEK pathway drugs is commonly observed in the treated cancer patients. A vital unmet need is the development of agents that potently and safely inhibit the altered KRAS signaling in these settings. A broadly acting KRAS mutation small molecule inhibitor lead series was developed using KRAS domain structure-guided scaffold modifications starting from a group of KRASG12C inhibitors. Optimized properties of these compounds were evaluated by tumor cell selectivity in vitro and pharmacophore elaboration. A novel lead series was identified with robust tumor cell growth inhibition, exemplified with the TEB-17112 lead candidate, having IC50 of inhibition against multiple KRAS-altered cell lines: NCI-H358 (KRAS-G12C, 33.6nM), AGS (KRAS-G12D, 23.5 nM), SW480 (KRAS-G12V, 22.5 nM) and A375 (KRAS-wildtype, 58.9 nM) respectively. TEB-17112 demonstrated inhibition of SW480 and H358 mouse xenografts at 25 or 50 mg/kg PO QD (21 days) without significant body weight loss. On further optimization of the lead series, TEB-17231 had on average a higher potency against KRAS mutant tumor cell lines, including H358 (12 nM), AGS (5.4 nM), SW480 (3.6 nM), and A427 (KRAS-G12D, 9.7 nM). With a candidate group of 7 compounds from this lead series, there was consistently a 5- to 6-fold selectivity of inhibition for KRAS mutant over KRAS wildtype cell lines. The lead candidate TEB-17231 was also observed to inhibit cell lines with other KRAS mutations: NCI-H1734 (KRAS-G13C, 6.5 nM), MDA-MB-231 (KRAS-G13D,11.2 nM), RPMI-8226 (KRAS-G12A, 11.3 nM), Calu-6 (KRAS-Q61K,19.8 nM), KP-2 (KRAS-G12R, 24.1 nM), LS123 (KRAS-G12S, 21 nM), as well as HRAS and NRAS mutant cell lines. TEB-17231 inhibits phospho-ERK downstream signaling in several tumor cell lines. Further, TEB-17231 exhibited tumor growth inhibition (IC50) in KRAS-G12C Ba/F3 (14 nM) and derivative cell lines that acquired resistance to G12C inhibitor MRTX849 by the additional KRAS domain mutations as follows: H95Q (32 nM), H95D (40 nM), Y96C (39 nM), Y96D (20 nM) and R68S (22 nM), compared with greater than 1μM for MRTX849. TEB-17231 induces late apoptosis of NCI-H358 cells in a manner that is time and concentration dependent. In addition to the improved selectivity and potency, TEB-17231 demonstrated satisfactory pharmacokinetics and oral bioavailability in mice (55%). Furthermore, with the SW480 (G12V) in vivo xenograft model, TEB-17231 showed clear tumor growth inhibition with QD dosing for 4-8 mg/kg PO without body weight loss. These properties highlight TEB-17231 as a potential clinically actionable inhibitor for the KRAS-modified tumor population and warrant investigation of TEB-17231 in combination with other agents in the future.

Citation Format: Zusheng Xu, David T. Weaver, Robert Drakas, Yangtong Lou. The small molecule KRAS inhibitor, TEB-17231, blocks tumor progression and overcomes KRASG12C inhibitor mediated resistance [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 2627.