Abstract C072: Discovery of highly potent and selective covalent inhibitors of FGFR4

Abstract

Hepatocellular carcinoma (HCC) accounts for 65% of all cases of liver cancers, ranking the 6th most common cancer and the 2nd cause of cancer mortality. HCC has more than 700,000 new cases/year and 600,000 deaths/year. Sorafenib is currently the standard of care for advanced disease, provides a response rate of ~2% and median survival <11 months. The fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4)-Klotho β (KLB) signaling pathway regulates bile acid synthesis and is also a key driver in certain subtypes of HCC (around 30%). We generated BGS2219 and BGS2223 through FGFR4 structure-based design. BGS2219 and BGS223 are potent, selective and irreversible FGFR4 inhibitors. BGS2219 inhibits FGFR4 with an IC50 of 4nM and has greater than 2500 fold selectivity over FGFR1, 2 and 3. BG2219 took effects in both HCC and RMS tumor cell lines. In vivo administration of BG2219 was well tolerated in mice at all dosages with no body weight loss and and inhibited tumor growth in a dose -dependent fashion in HCC xenograft model. Complete tumor regression was observed at 40mg/kg. BGS2219 was tested in a combo therapy regimen with R1507 (anti-IGFR1 mab) in RMS (rhabdomyosarcoma) xenograft model in mice and showed that BG2219 plus R1507 significantly reduce the tumor volume in comparison with R1507 alone. BGS2223 is derived from BG2219, with improved oral bioavailability. BGS2223 has no hit in Cerep Screen safety panel and no activity detected in hERG assay at 10mM. In vivo oral administration of BG2223 in mice was well tolerated with no body weight loss and showed dose-dependent tumor growth inhibition in HCC CDX model at all dosages. Tumor regression was achieved at high dose treatment. BGS22 treatment in vivo in HCC tumor bearing mice caused alteration of CYP7A1 and FGF19 expression, which were utilized as biomarkers for FGFR4 inhibition. Citation Format: Hang Chen, Katherine Slemmons, Heather Ha, Robert Stanley, Qian Cai, Irene Yuan, Lee Helman, Ping Cao. Discovery of highly potent and selective covalent inhibitors of FGFR4 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C072. doi:10.1158/1535-7163.TARG-19-C072