The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

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.

Futibatinib Is a Novel Irreversible FGFR 1–4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors

“…Together, these results suggested that the risk of drug resistance with futibatinib was low and infigratinib, which showed strong inhibition of FGFR1-3, but only marginal inhibition of FGFR4 in earlier studies (36,38,39). Similarly, PRN1371 has been reported to exhibit a 50-fold lower affinity for FGFR4 than for FGFR1-3 (26). Because futibatinib is a covalent inhibitor, it was expected that its inhibitory activity would persist even after short periods of exposure in the cells, as has been observed with other covalent inhibitors (26,41).…”

“…Similarly, PRN1371 has been reported to exhibit a 50-fold lower affinity for FGFR4 than for FGFR1-3 (26). Because futibatinib is a covalent inhibitor, it was expected that its inhibitory activity would persist even after short periods of exposure in the cells, as has been observed with other covalent inhibitors (26,41). However, as FGFR turnover was determined to be rapid (half-life ~4 hours) in the cell lines used in our study, the duration of futibatinib inhibition could not be accurately estimated.…”

“…Covalently binding kinase inhibitors inhibit kinase activity irreversibly and may achieve superior potency along with a longer duration of action compared with conventional reversible ATP-competitive inhibitors (21,24,25). Despite these potential advantages, the with PRN1371 among the few currently under clinical investigation (26).…”

“…Futibatinib demonstrated remarkable selectivity for FGFR among 296 kinases and was found to bind covalently to the FGFR kinase domain. The binding mode of futibatinib to FGFR was shown to be quite different from known reversible ATP-competitive FGFR inhibitors, such as AZD4547, infigratinib, erdafitinib, or pemigatinib, orirreversible FGFR inhibitors such as PRN1371(26,32,36,37). Recent structural analysis of the futibatinib-FGFR complex revealed that futibatinib targets the P-loop in the ATP-binding pocket of the FGFR tyrosine kinase domain, forming a rapid covalent adduct with a unique cysteine upon contact(32).…”

“…landscape.There are several irreversible FGFR inhibitors currently under investigation. PRN1371, which demonstrated robust FGFR1-3 inhibitory activity in preclinical experiments, has also been reported to potently inhibit several FGFR2 and FGFR3 drug-resistant mutants, but was shown to have reduced activity against the common drug-resistant gatekeeper mutant (V561M) of FGFR1(26).A phase 1 trial (NCT02608125) of this drug is ongoing in patients with advanced tumors. FINN-2 and FINN-3 are irreversible FGFR inhibitors that have demonstrated in vitro inhibition of FGFR1 and FGFR2 gatekeeper mutants but have not yet been tested in the clinic (47).…”