INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models

• DOI: 10.1371/journal.pone.0231877
• Publication Date: 2020-04-21T20:27:27Z
• Authors: Phillip C. C. Liu; Holly Koblish; Liangxing Wu; Kevin Bowman; Sharon Diamond; Darlise DiMatteo; Yue Zhang; Michael Hansbury; Mark Rupar; Xiaoming Wen; Paul Collier; Patricia Feldman; Ronald Klabe; Krista A. Burke; Maxim Soloviev; Christine Gardiner; Xin He; Alla Volgina; Maryanne Covington; Bruce Ruggeri; Richard Wynn; Timothy C. Burn; Peggy Scherle; Swamy Yeleswaram; Wenqing Yao; Reid Huber; Gregory Hollis
• Keywords: Tolerability

Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has established early clinical trials FGFR inhibitors. Here, we present the molecular structure preclinical characterization INCB054828 (pemigatinib), a novel, selective inhibitor 1, 2, 3, currently phase 2 trials. pharmacokinetics pharmacodynamics were investigated using cell lines tumor models, antitumor effect oral was xenograft models with genetic alterations FGFR1, or 3. Enzymatic assays recombinant human kinases showed potent inhibition 3 by (half maximal inhibitory concentration [IC50] 0.4, 0.5, 1.0 nM, respectively) weaker activity against FGFR4 (IC50 30 nM). selectively inhibited activation signaling compared lacking aberrations. The pharmacokinetic profile suggests target is achievable vivo low doses. suppressed xenografted monotherapy, combination cisplatin provided significant over either single agent, an acceptable tolerability. data presented for INCB054828, together preliminary observations, support continued investigation patients alterations, such fusions activating mutations.