No abstract

A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3. The chemical modifications, which were guided by 3D-modeling analyses of the inhibitor and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3. In in vitro studies and xenograft models in mice, 8 shows antitumor activity against cancer cell lines that harbor genetically altered FGFRs. These results support the potential therapeutic use of 8 as a new anticancer agent.

Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) comprises four members (FGFR1-4). FGFRs regulate multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations, as well as overexpression, drive activation of both kinase activity of the receptors and the pathway signaling, which is associated with tumor growth and survival. Therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of CH5183284/Debio 1347, an orally available and selective inhibitor of FGFR1, 2, and 3. The lead compound CH5183284/Debio 1347 was identified from our original compound library by a high throughput screening program. Chemical modifications, which were guided by 3D-modeling analyses of the lead series and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3 (IC50: 9.3 nM, 7.6 nM, and 22 nM), but does not effectively inhibit FGFR4 (IC50: 290 nM), KDR (IC50: 2,100 nM) nor other 34 kinases. To evaluate kinase selectivity further, we used a KINOMEscan panel consisting of 442 kinases including some mutated forms of kinases. At 100 nM, CH5183284/Debio 1347 only bound to 5 kinases in the panel including FGFR1, FGFR2, and FGFR3 (over 80% inhibition to an ATP analog binding). An X-ray crystal structure analysis showed CH5183284/Debio 1347 binding to the ATP-binding site of FGFR1 in DFG-in mode and its interaction with both the hinge region and the backpocket of the protein. CH5183284/Debio 1347 also showed antitumor activity against cancer cell lines harboring genetic alterations in FGFRs in vitro and in xenograft models in mice. In addition, the unique ability of CH5183284/Debio 1347 to inhibit a relevant FGFR2 gatekeeper mutant (V564F) was documented in cellular phosphorylation assays, in vitro cell proliferation assays, and in vivo efficacy studies in a xenograft mouse model. The X-ray crystal structure analysis and modeling studies of the inhibitors, including NVP-BGJ398 and AZD4547, with FGFRs that were used to guide the SAR strategy in the optimization program will be presented and discussed, together with the unique susceptibility of CH5183284/Debio 1347 against a gatekeeper mutant of FGFR2. These findings underline the therapeutic potential of CH5183284/Debio 1347 in patients with FGFR genetic alterations and are the basis for an ongoing early clinical trial in several cancer types. Citation Format: Hirosato Ebiike, Naoki Taka, Yoshito Nakanishi, Nukinori Akiyama, Fumie Sawamura, Kenji Morikami, Masayuki Matsushita, Masayuki Ohmori, Kyouko Takami, Ikumi Hyohdoh, Masami Kohchi, Tadakatsu Hayase, Hiroki Nishii, Nobuya Ishii, Hiroharu Matsuoka. Design and preclinical profile of CH5183284/Debio 1347, a novel orally available and selective FGFR inhibitor acting on a gatekeeper mutant of FGFR2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2533. doi:10.1158/1538-7445.AM2014-2533