Abstract LB317: Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations

Abstract

Abstract Introduction: FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations. Method: ABSK121 was evaluated in biochemical and cellular proliferation experiments for its inhibition on wile type FGFR enzymatic activity and FGFR-dependent cancer cell proliferation. Its potency against FGFR mutations was also analyzed in relevant biochemical and cellular experiments. Efficacy studies were conducted in multiple tumor models to confirm its in vivo activities. Preliminary selectivity profile and ADME profiles were also evaluated. Results: ABSK121 inhibited wild type FGFRs with IC50<10 nM in biochemical assay. ABSK121 also displayed great potency against resistant kinase domain mutations. In cell lines harboring FGFR amplification, fusions, or resistant mutations, ABSK121 demonstrated strong anti-proliferation activity as well as strong inhibition of FGFR downstream signaling activities. In preclinical in vivo studies, oral administration of ABSK121 strongly inhibited the growth of subcutaneous xenograft tumors dependent on wild type or resistant mutant FGFR. Suppression of tumor growth was dose-dependent and well correlated with pharmacodynamic inhibition of FGFR signaling. ABSK121 also showed great kinase selectivity with no CYP or hERG inhibition. Conclusion: ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development. Citation Format: Haiyan Ying, Wenqun Xin, Haibing Deng, Yuan Zhao, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB317.