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

Abstract

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

• 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
• Journal: PloS one (PLoS One) Vol. 15 Issue 4 Pg. e0231877 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 32315352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Morpholines
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Receptor, Fibroblast Growth Factor, Type 1
• Receptor, Fibroblast Growth Factor, Type 2
• Receptor, Fibroblast Growth Factor, Type 3
• pemigatinib

Topics

• Administration, Oral
• Animals
• Cell Line, Tumor
• Female
• Half-Life
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Mice, SCID
• Morpholines (chemistry, pharmacokinetics, therapeutic use)
• Neoplasms (drug therapy, pathology)
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, therapeutic use)
• Pyrimidines (chemistry, pharmacokinetics, therapeutic use)
• Pyrroles (chemistry, pharmacokinetics, therapeutic use)
• Rats
• Rats, Nude
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, metabolism)
• Receptor, Fibroblast Growth Factor, Type 2 (antagonists & inhibitors, metabolism)
• Receptor, Fibroblast Growth Factor, Type 3 (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays