Abstract 5582: Discovery and preclinical characterization of ISM8001, a covalent and selective FGFR2/FGFR3 dual inhibitor with strong monotherapy anti-tumor activity against advanced solid tumors
Authors: Zhang Yihong , Wang Yazhou , Cai Xin , Liu Jinxin , Cui Hui , Qiao Junwen , Lin Xiaoxia , Ding Xiao , Bavadekar Supriya , Rao Sujata , Zhang Man , Ren Feng , Zhavoronkov Alex 
Published: March 2024

Abstract
Oncogenic alterations in fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3) are key drivers in intrahepatic cholangiocarcinoma, urothelial carcinoma and multiple other solid tumors. Currently approved pan-FGFR inhibitor therapy is limited by off-isoform toxicity (FGFR1-mediated hyperphosphatemia and FGFR4-mediated diarrhea) and acquired FGFR2 or FGFR3 kinase domain resistance mutations. The second generation of FGFR inhibitors currently undergoing clinical evaluation such as RLY-4008 and LOXO-435 are primarily focused on achieving selectivity against either the FGFR2 or FGFR3 isoform, which may narrow their clinical potential. To overcome this limitation and to allow a favorable toxicity profile, we designed and evaluated the anti-cancer effects of a novel and selective FGFR2/FGFR3 dual inhibitor, ISM8001. Biochemically, ISM8001 showed superior inhibition against FGFR2 and FGFR3 with &gt;90-fold and &gt;800-fold selectivity of FGFR2 over FGFR1 and FGFR4, respectively. As an irreversible inhibitor, ISM8001 displayed strong affinity and high efficiency of covalent bond formation with FGFR2/3. Additionally, ISM8001 showed broad inhibition against multiple FGFR2/3 mutant isoforms, especially gatekeeper mutation (FGFR2-V564F and FGFR3-V555M). ISM8001 inhibited cell proliferation of multiple human cancer cell lines with FGFR2/3 aberration with IC50 &lt;10 nM while IC50 &gt;1 µM was observed in cell lines without FGFR2/3 alterations. Furthermore, ISM8001 demonstrated robust in vivo anti-tumor efficacy in multiple cell line-derived xenograft mouse models including the SNU-16 gastric cancer model (FGFR2-amplification), the AN3CA endometrial cancer model (FGFR2 N549K mutation) and the RT4 bladder cancer model (FGFR3-fusion), with tumor growth inhibition varying from 80%~120% while no significant serum phosphate increase or body weight loss. ISM8001 also displayed strong anti-tumor effects in xenograft models of Ba/F3-FGFR2/3 engineered cell lines with different gatekeeper mutations. ISM8001 is classified as a BCS II compound with favorable DMPK properties and druggability, high permeability, low efflux ratio and low DDI risk. In vivo PK profiles showed moderate to low clearance and high oral bioavailability across preclinical species. In addition, ISM8001 showed a promising in vitro safety profile with favorable selectivity in 468-kinase and Cerep-44 panel studies, and no hERG concerns. Results of 28-day non-clinical toxicology studies in rat and dog showed a safety window of approximately 2-5 fold based on efficacious exposure in different models. Taken together, these data support the clinical development of ISM8001 as a novel, selective FGFR2/FGFR3 dual inhibitor for the potential tissue-agnostic therapy of advanced solid tumors with FGFR2/3 aberrations.
Citation Format: Yihong Zhang, Yazhou Wang, Xin Cai, Jinxin Liu, Hui Cui, Junwen Qiao, Xiaoxia Lin, Xiao Ding, Supriya Bavadekar, Sujata Rao, Man Zhang, Feng Ren, Alex Zhavoronkov. Discovery and preclinical characterization of ISM8001, a covalent and selective FGFR2/FGFR3 dual inhibitor with strong monotherapy anti-tumor activity against advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5582.