Abstract SY30-01: Discovery of the highly selective covalent FGFR1-4 inhibitor PRN1371, currently in development for the treatment of solid tumors
Authors: Brameld Ken A. 
Published: July 2016

Abstract
Discovering drug candidates that exhibit durable on-target pharmacology upon oral dosing has been extremely challenging for the pharmaceutical industry. The introduction of a covalent bond between a small molecule drug and its pharmacological target has the potential to achieve prolonged target inhibition with minimal systemic drug exposure. Several irreversible covalent inhibitors employing this strategy have been approved or are in late stage clinical development for the treatment of various cancer indications such as multiple myeloma (carfilzomib), lymphoma (ibrutinib), lung cancer (afatinib) and breast cancer (neratinib). However, the discovery process for covalent drugs presents unique challenges. Identification and optimization of lead molecules require screening assays that measure the degree of covalent engagement with the target, both in vitro and in vivo. In addition, the reactive chemistries often employed for covalent bonding can impart poor ADME properties, requiring IV administration or high oral doses. Principia Biopharma, a pioneer in covalent drug discovery and development, has overcome many of these challenges in the discovery of PRN1371, a covalent irreversible inhibitor of fibroblast growth factor receptor (FGFR) 1-4 with long target residence time.
Aberrant signaling of the FGF/FGFR pathway is an oncogenic driver in many solid tumors. Early reports from Phase 1/2 studies with reversible ATP competitive inhibitors have demonstrated encouraging efficacy from FGFR inhibition in the treatment of bladder, lung, and breast cancers. However, some results are difficult to interpret due to the poor selectivity of the drugs used. Aberrant pathway activation may be a consequence of FGF ligand overexpression or changes to the FGF receptor including mutations, translocations/fusions, and protein overexpression. Such genetic alterations in one or more isoforms of FGFR have been reported in many solid tumors including bladder, breast, cervical, endometrial, gastric, hepatocellular, lung, and ovarian cancers. There remains a compelling medical need to identify a highly selective inhibitor of all four FGFR family members, FGFR1-4, to improve clinical responses in patients while minimizing off-target toxicity.
PRN1371 is the culmination of a drug discovery program focused upon the creation of an oral, low dose, highly selective, potent, and irreversible inhibitor of FGFR1-4. Starting from a 7-oxopyridopyrimidine core, a series of covalent inhibitors were designed to incorporate a Michael acceptor appropriately positioned to engage Cys 488 in a covalent bond. Extensive SAR was generated using a FRET-based biochemical occupancy assay to measure the durability of drug binding over time. Molecules were optimized for prolonged FGFR residence time and potent inhibition of pERK in HUVEC cells upon FGF stimulation. Advanced leads with suitable cellular potency were studied in vivo, using an FGF-induced CCL2 readout in mice. The relationship between plasma drug concentration (PK) and pharmacological inhibition of CCL2 production (PD) in mice provided essential guidance in selecting optimal drug candidates. To assess the ADME liabilities of the Michael acceptor, in vitro microsomal stability and thiol reactivity assays were used. The final selection of PRN1371 as a clinical candidate was based upon the ideal combination of exquisite selectivity, potent and prolonged pharmacodynamic inhibition of FGFR1-4 in vivo and high predicted human oral bioavailability. PRN1371 is now evaluated in a Phase 1/2 open-label, multicenter clinical trial for solid tumors (ClinicalTrials.gov: NCT02608125).
Citation Format: Ken A. Brameld. Discovery of the highly selective covalent FGFR1-4 inhibitor PRN1371, currently in development for the treatment of solid tumors. [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 SY30-01.