Abstract
The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations.
Highlights
In recent years, the use of molecular-targeted agents is increasingly adopted in basic and clinical cancer research with some of these drugs, improving patient survival times
To investigate the selectivity of CH5183284/Debio 1347 against FGFR1, FGFR2, and FGFR3, we screened CH5183284/Debio 1347 for activity against the FGF receptors (FGFR) family members and its selectivity among 20 tyrosine kinases and 14 serine/threonine kinases in a cell-free system (Table 1)
Because the IC50 for kinase insert domain receptor (KDR) kinase was 2,100 nmol/L, these data indicate that CH5183284/Debio 1347 could distinguish FGFR1, FGFR2, and FGFR3 from FGFR4 and KDR at the enzyme level
Summary
The use of molecular-targeted agents is increasingly adopted in basic and clinical cancer research with some of these drugs, improving patient survival times In this context, a number of agents that target tyrosine kinases have been launched, such as the EGF receptor (EGFR) inhibitor erlotinib, the anti-HER2 antibody trastuzumab, the BCR-ABL inhibitor imatinib, the BRAF inhibitor vemurafenib, and the ALK inhibitor crizotinib. A number of agents that target tyrosine kinases have been launched, such as the EGF receptor (EGFR) inhibitor erlotinib, the anti-HER2 antibody trastuzumab, the BCR-ABL inhibitor imatinib, the BRAF inhibitor vemurafenib, and the ALK inhibitor crizotinib Each of these agents has demonstrable efficacy when used in patient cohorts that are stratified on the basis of the genetic status of their respective molecular targets. There is a clear clinical need for FGFR-selective inhibitors
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