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From fragment to lead: de novo design and development toward a selective FGFR2 inhibitor

DOI: 10.1021/acs.jmedchem.1c01163 DOI Help

Authors: Lewis D. Turner (University of Leeds) , Chi H. Trinh (University of Leeds) , Ryan A. Hubball (University of Leeds) , Kyle M. Orritt (University of Leeds) , Chi-Chuan Lin (University of Leeds) , Julie E. Burns (University of Leeds) , Margaret A. Knowles (University of Leeds) , Colin W. G. Fishwick (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 46

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 15378

Open Access Open Access

Abstract: Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.

Journal Keywords: Amides; Peptides and proteins; Inhibitors; Conformation; Selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 16/11/2021 20:42


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)