Abstract
An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668-76. ©2017 AACR.
Highlights
The fibroblast growth factor receptors (FGFR) are a family of receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4) important for many physiologic processes including development, angiogenesis, and homeostasis [1, 2]
Optimization of an attractive lead series was guided by both an FGFR1 enzyme activity assay and an FGFR1 biochemical occupancy assay that provided a readout on covalent cysteine engagement; the detailed SAR and medicinal chemistry involved in this work has been published elsewhere [8]
The effort culminated in the identification of PRN1371 (Fig. 1A) as a potent, selective, and covalent inhibitor of FGFR1, FGFR2, FGFR3, and FGFR4
Summary
The fibroblast growth factor receptors (FGFR) are a family of receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4) important for many physiologic processes including development, angiogenesis, and homeostasis [1, 2]. The binding of an FGF to an FGFR results in receptor dimerization and transphosphorylation of tyrosine kinase domains, leading to activation of downstream signaling pathways [3]. Genetic alterations of FGFR, including mutations, fusions, and gene amplification, lead to aberrant signaling pathway activation and drive cancer growth. Genetic alterations of FGFR have been detected in multiple cancer types, including urothelial, squamous non–small cell lung (NSCLC), squamous head and neck cancer, cholangiocarcinoma, and breast cancer [4,5,6]. Emerging clinical data with multiple FGFR inhibitors have validated this target as a potential anticancer therapeutic. The first FGFR inhibitors to be assessed in the clinic were nonselective FGFR inhibitors, such as dovitinib and ponatinib, of which both on-target and off-target activities likely contributed to clinical
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