VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signaltargeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI 50 > 10 mmol/L) in VEGFR signal-or MET signalindependent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685-96. Ó2013 AACR.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1−4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I−III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

<p>PDF - 243KB, Supplementary Figure S1. Growth inhibition of TAS-115 against MET amplified cancer cell lines. Supplementary Figure S2. Kinase inhibitor-induced cell damage in rat cardiomyocytes after 96 h of treatment. Supplementary Figure S3. Gene expression changes in mice bearing human gastric cancer SC-9 after TAS-115 or sunitinib treatment. Supplementary Figure S4. Anti-tumor efficacy of TAS-115 against athymic mice transplanted with MET-amplified human gastric cancer Hs746T (A), NUGC-4 (B). Supplementary Figure S5. The inhibitory activity of sunitinib against adenosine monophosphate (AMP)-activated protein kinase (AMPK). Supplementary Table S1. Kinase inhibitory activity of TAS-115 and sunitinib against 192 kinases. Supplementary Table S2. Cell growth inhibition of TAS-115, sunitinib, sorafenib and crizotinib against MET-amplified or MET-inactivated cancer cell lines. Supplementary Table S3. Median survival times (MST) in the NUGC-4 peritoneal dissemination model after TAS-115 or sunitinib treatment.</p>

<p>PDF - 243KB, Supplementary Figure S1. Growth inhibition of TAS-115 against MET amplified cancer cell lines. Supplementary Figure S2. Kinase inhibitor-induced cell damage in rat cardiomyocytes after 96 h of treatment. Supplementary Figure S3. Gene expression changes in mice bearing human gastric cancer SC-9 after TAS-115 or sunitinib treatment. Supplementary Figure S4. Anti-tumor efficacy of TAS-115 against athymic mice transplanted with MET-amplified human gastric cancer Hs746T (A), NUGC-4 (B). Supplementary Figure S5. The inhibitory activity of sunitinib against adenosine monophosphate (AMP)-activated protein kinase (AMPK). Supplementary Table S1. Kinase inhibitory activity of TAS-115 and sunitinib against 192 kinases. Supplementary Table S2. Cell growth inhibition of TAS-115, sunitinib, sorafenib and crizotinib against MET-amplified or MET-inactivated cancer cell lines. Supplementary Table S3. Median survival times (MST) in the NUGC-4 peritoneal dissemination model after TAS-115 or sunitinib treatment.</p>