2. Academic Validation
  3. Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach

Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach

  • ACS Med Chem Lett. 2023 Feb 28;14(3):312-318. doi: 10.1021/acsmedchemlett.3c00003.
Minh H Nguyen 1,  Hai-Fen Ye 1,  Yao Xu 1,  Lisa Truong 1,  April Horsey 1,  Peng Zhao 1,  Evan D Styduhar 1,  Michelle Frascella 1,  Lynn Leffet 1,  Kelly Federowicz 1,  Elham Behshad 1,  Anlai Wang 1,  Ke Zhang 1,  Michael R Witten 1,  Chao Qi 1,  Ravi Jalluri 1,  Cheng-Tsung Lai 1,  Onur Atasoylu 1,  Jennifer J Harris 1,  Rodrigo Hess 1,  Luping Lin 1,  Guofeng Zhang 1,  Maryanne Covington 1,  Sharon Diamond 1,  Wenqing Yao 1,  Oleg Vechorkin 1
Affiliations

Affiliation

  • 1 Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
PMID: 36923909 DOI: 10.1021/acsmedchemlett.3c00003
Abstract

Fibroblast Growth Factor receptors (FGFRs) are transmembrane Receptor Tyrosine Kinases that regulate multiple physiological processes. Aberrant activation of FGFR2 and FGFR3 has been linked to the pathogenesis of many tumor types, including cholangiocarcinoma and bladder Cancer. Current therapies targeting the FGFR2/3 pathway exploiting small-molecule kinase inhibitors are associated with adverse events due to undesirable inhibition of FGFR1 and FGFR4. Isoform-specific FGFR2 and FGFR3 inhibitors that spare FGFR1 and FGFR4 could offer a favorable toxicity profile and improved therapeutic window to current treatments. Herein we disclose the discovery of dual FGFR2/FGFR3 inhibitors exploiting scaffold repurposing of a previously reported ALK2 tool compound. Structure-based drug design and structure-activity relationship studies were employed to identify selective and orally bioavailable inhibitors with equipotent activity toward wild-type kinases and a clinically observed gatekeeper mutant.

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