From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor

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 Hbond which could be utilized to design more selective FGFR2 inhibitors.

Fragment-to-Lead Medicinal Chemistry Publications in 2021

“…However, there are no table entries for papers targeting proteases, the first time this target class has not been represented. In contrast, there are more examples of GPCR case studies in Table than in previous years (entries 26, 27, and 28), including the description of the discovery of the M1 agonist clinical compound HTL9936 (entry 28). …”

“…Notable examples include the NMR-based fragment screen against regulatory RNA elements of SARS-CoV-2 50 and the use of NMR to identify fragments that bind to structured RNAs. 51 Additionally, fragment screening against 14 RNA targets has been undertaken using 19 F NMR, illustrating the potential utility of fragment screening to identify selective RNA binders. 52 We look forward to see if this and future work results in successful F2L campaigns.…”

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

“…Instead, a flexible loop in FGFR1/2 validated from MD simulation might be the cause of the selectivity. It is encouraging that a recent de novo design by Turner et al (2021) has provided a paradigm for perhaps the next-generation member of FGFR-specific inhibitors. They started from a fragment with moderate potency and carried out iterative rounds of de novo design as well as a classical SAR study to generate compound 31 .…”

Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation

“…Recently, an indazole-based inhibitor (compound 38) has been discovered that exhibits markedly reduced inhibition towards FGFR2 compared to FGFR1 [ 28 ]. Compound 38 specifically inhibited FGFR2 with an IC 50 of 29 nM, whereas it had an IC 50 of 389 nM against FGFR1 and 758 nM against FGFR3, exhibiting a 13-fold selectivity preference for FGFR2 over FGFR1.…”