Introduction:

Multiple human cancers harbor alterations in FGFRs that drive tumor growth, including mutations, translocations and amplifications. We developed a covalent, irreversible, highly selective FGFR1, 2, 3 and 4 inhibitor, PRN1371, by targeting a cysteine residue within the kinase domain. This approach enables highly selective and sustained inhibition of FGFR which extends well beyond circulating drug concentrations. PRN1371 is currently in a phase 1 clinical trial for the treatment of solid tumors.

Materials and Methods:

FGFR1-4 enzymatic activities were measured using the Caliper microfluidics Labchip system. Inhibition of proliferation was assessed over 3 days using Cell-Titer-Glo. SNU16 and RT4 xenograft tumor models were used to investigate pharmacodynamics and efficacy. For tumor inoculation, cancer cells were implanted into the rear flank of immunocompromised mice. Once tumor volume reached a mean average of 175mm3, mice were randomized and treated with FGFR inhibitor.

Results:

PRN1371 is a novel investigative drug that is a potent ATP competitive, highly selective inhibitor of the FGFR family of protein kinases. PRN1371 binds irreversibly to FGFR1, 2, 3 and 4, leading to long duration of target inhibition. The IC50 values for FGFR1, 2, 3 and 4 are 0.7, 1.3, 4.1 and 19.2 nM, respectively. The IC50 values are 55.0, 12.0, 1.2 and 2.3 nM for FGFR3-V555M, FGFR2-N549H, FGFR3-G697C and FGFR3-K650E, respectively. PRN1371 exhibited no significant activity against 247 other protein kinases. PRN1371 demonstrates potent inhibition of cell proliferation in multiple tumor cell lines driven by dysregulated FGFR signaling. In RT4, RT112, SNU16, AN3-CA, LI7, JHH7, and OPM2 cells, EC50's are 4.0, 4.1, 2.6, 43.3, 33.1, 231 and 14.0 nM, respectively.

PRN1371 is rapidly and well-absorbed. Bioavailability is dose and species-dependent.

PRN1371 demonstrates potent tumor growth inhibition and regression in FGFR3-fusion expressing RT4 and FGFR2-amplified SNU16 xenograft models, when dosed either continuously, or intermittently, and is generally well-tolerated. PRN1371 is also shown to have significant anti-tumor activity against a panel of PDX tumor xenografts of various lineages harboring different FGFR pathway alterations.

The phase 1 clinical trial will evaluate ascending doses of PRN1371 in a conventional “three plus three” design. Expansion cohorts of selected tumor types will then be investigated at the recommended dose level.

Conclusion:

PRN1371 is a potent, highly selective, irreversible inhibitor exhibiting sustained inhibition of FGFR 1, 2, 3 and 4. A Phase 1 clinical trial of PRN1371 for the treatment of solid tumors is currently ongoing.

Citation Format: Eleni Venetsanakos, Michael Bradshaw, David M. Goldstein, Kwan Leung, Dane Karr, Yan Xing, Jacob LaStant, Philip Nunn, Jin Shu, Abha Bommireddi, Steven G. Gourlay, Jens Oliver Funk, Ken A. Brameld. PRN1371, an irreversible, covalent inhibitor of FGFR1, 2, 3 and 4 is highly efficacious in preclinical tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1249.