Abstract 6321: HMPL-453, a highly selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays potent activity in FGFR-altered tumor models
Authors: Hu Jia , Ni Jun , Jiao Longxian , Zhou Jinghong , Fan Shiming , Tang Renxiang , Zhang Wei , Ge Xuelei , Zhang Qihang , Yu Juntao , Yu Ying , Shi Dongxia , Cheng Min , Xue Weifang , Xia Sumei , Zhong Zeyu , Wang Jian , Sai Yang , Qing Weiguo , Dai Guangxiu , Ren Yongxin , Shi Michael , Su Weiguo 
Published: June 2023

Abstract
Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Dysregulation of FGFR signaling due to receptor fusion, mutation or amplification is observed across multiple cancer types, making activated FGFRs an important therapeutic target. Herein, we present the preclinical characterization of HMPL-453, a highly potent and selective inhibitor of FGFR1, 2, and 3, discovered and being currently developed in phase II clinical trial (NCT04353375) by HUTCHMED.
Methods: Kinase activity was measured by Transcreener™ Fluorescence Polarization assay or Z’-LYTE kinase assay. In vitro anti-proliferation activity was measured by CellTiter-Glo luminescent or CCK-8 assay. The effect of HMPL-453 on FGFR signaling pathway was detected by western blot. Multiple tumor models with FGFR alteration were applied in Nu/Nu nude mice to determine anti-tumor efficacy of 453 as a single agent. A model in immune-competent BALB/c mice inoculated with the constructed NIH/3T3 cells carrying FGFR2-AHCYL1 fusion was chosen to investigate the combination effect of HMPL-453 with anti-PD-1 antibody.
Results: HMPL-453 potently inhibited the tyrosine kinase activities of recombinant FGFR 1, 2, and 3 in vitro (IC50 values of 6, 4, and 6 nM, respectively) with weaker activity against FGFR4 (IC50 = 425 nM). HMPL-453 selectively inhibited proliferation of tumor cell lines with dysregulated FGFR signaling (GI50s: 3~105 nM) compared with cell lines lacking FGFR aberrations (GI50s &gt; 1.5 µM). HMPL-453 demonstrated strong inhibition of phosphorylation of FGFR and downstream protein in tumor cell lines harboring FGFR2 fusion. Oral administration of HMPL-453 could induce time- and dose-dependent inhibition of phosphorylation of FGFR and resulted in remarkable and dose-dependent anti-tumor activity in multiple FGFR-altered tumor models. HMPL-453 at the dose of 50 mg/kg/day could induce tumor regression in most tumor models tested. Moreover, HMPL-453 significantly improved anti-tumor activity of anti-PD-1 antibody in a FGFR2 fusion model by priming the immune environment.
Conclusion: HMPL-453 is a highly potent and selective inhibitor of FGFR 1, 2, and 3 with strong activity against FGFR-deregulated tumors in preclinical models, supporting continued investigation in patients with FGFR alterations (such as fusion and mutation) either as a single agent or in combination with PD-1 blockade.
Citation Format: Jia Hu, Jun Ni, Longxian Jiao, Jinghong Zhou, Shiming Fan, Renxiang Tang, Wei Zhang, Xuelei Ge, Qihang Zhang, Juntao Yu, Ying Yu, Dongxia Shi, Min Cheng, Weifang Xue, Sumei Xia, Zeyu Zhong, Jian Wang, Yang Sai, Weiguo Qing, Guangxiu Dai, Yongxin Ren, Michael Shi, Weiguo Su. HMPL-453, a highly selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays potent activity in FGFR-altered tumor models [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 6321.