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Ref Type Abstract
PMID
Authors Gong Li; Alexander Drilon; Shengxiang Ren; Peilong Zhang; Xiangqiu Li; Linna Li; Ruiya Zhang; Wenli Lan; Di Han; Weizhe Xue; Peipei Yang; Shutan Liao; Kevin Schaab; Brendan Putz; Hepeng Shi
Title Abstract 828: ANS03, a novel, orally bioavailable small-molecule type II ROS1/NTRK inhibitor, effectively overcomes clinically relevant ROS1/NTRK resistance mutations and exhibits potent antitumor activity in preclinical tumor models
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 85 8_Supplement_1 April 21 2025 828 Cancer Res
URL https://aacrjournals.org/cancerres/article/85/8_Supplement_1/828/755303
Abstract Text Background: ROS1 and NTRK are critical driver genes for tumorigenesis and progression, and inhibitors targeted towards their tyrosine kinases (TKIs) are clinically proven anti-cancer agents. Although Type I ROS1/NTRK TKIs like Repotrectinib show clinical benefit, on-target resistance mutations inevitably develop. Hence there is an unmet clinical need for novel Type II ROS1/NTRK TKIs capable of overcoming on-target acquired resistance mutations. Methods: A comprehensive panel of IND-enabling non-clinical studies was conducted to evaluate the mechanism of action, pharmacologic activity, pharmacokinetics, and the safety profile of ANS03. Results: ANS03 is a novel Type II TKI targeting both ROS1 and NTRK. Unlike type I TKIs, which engage the active “DFG-in” conformation of the kinase, type II TKIs engage the inactive “DFG-out” conformation of the kinase and also extend into an adjacent allosteric pocket. As a result, ANS03 shows a broad and potent inhibitory spectrum for ROS1/NTRK drug-resistance mutations with IC50’s ranging from 0.324 nM to 4.88 nM. In cellular systems, ANS03 showed outstanding antitumor effects against wild-type fusions and diverse acquired drug-resistance mutations, with IC50’s ranging from 0.1 nM to 26 nM. For ROS1 SF mutations (G2032R, D2033N), ANS03 was 22.2x and 30.6x more active than Repotrectinib, respectively. ANS03 showed a 104x enhancement against ROS1 Cβ6 mutation (L2086F), a 52.5x enhancement against NTRK1 xDFG mutation (G667C), and a 104.4x enhancement against NTRK1 compound mutation (G595R-G667C) vs. Repotrectinib. ANS03 also had better activity against the ROS1 L2086F mutation when compared to both Repotrectinib and NVL-520. In vivo, ANS03 exhibited antitumor effects in BALB/c nude mouse subcutaneous xenotransplantation models that were as good- or better than- those of the ROS1/NTRK TKIs Repotrectinib or NVL-520. Notably, it achieved complete tumor regression in Ba/F3-ROS1-G2032R models at a dose of 10 mg/kg and triggered tumor regression in LU-01-0414 (ROS1 wild-type fusion) and KM12-Luc (NTRK wild-type fusion) models at a dose of 3 mg/kg. Moreover, ANS03 significantly improved the survival rates of tumor bearing mice in a dose-dependent manner. Concurrent pharmacokinetic (PK) studies in mice positively correlated plasma exposures of ANS03 to administered doses, with ANS03 showing favorable tumor distribution and detectable brain penetration. Conclusion: Non-clinical studies of ANS03 showed it is a potent, orally bioavailable Type II ROS1/NTRK inhibitor with remarkable activity against various pathogenetic ROS1/NTRK alterations and with favorable absorption, distribution, pharmacokinetics, efficacy, and tolerability profiles in vivo. The compound will enter Phase 1 clinical development in the US and China soon.

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