2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4

Abstract

As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity.

Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors

“…Indeed, H3B-6527 [56], BLU-9931 [84], BLU-554 [84] and FGF401 [90] were developed as FGFR4-selective covalent inhibitors that target C552 for irreversible binding (Figure 4E). Among these four molecules, FGF401 is the most interesting because the covalent bond it forms is reversible, which reduces the off-target effect and prolongs the residence time [91,92]. The crystal structure of FGF401/FGFR4 was recently reported by our laboratory (PDB ID 6JPJ) [57], and its potential utility is currently under intensive research.…”

A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives

“…[1] Compoundsw ith higherF sp 3 values tend to possess more drug-like properties sucha sh igh solubility and low promiscuity, [2] and these compounds are more likely to achieve clinicals uccess.I ndeed, by enhancing the Fsp 3 values in the courseo fl ead optimization, many research groups succeeded in improving physicalp roperties of candidate compounds. [3][4][5][6] As as tartingp oint for drug development, the acquisition of ac ompound with ah igh Fsp 3 value is desirable. However,c urrent screening libraries have fewer saturated carbonsd ue to the typical reactions used to preparet he compounds:a mide bond formation and cross-coupling reaction.…”

“…Compounds with higher Fsp 3 values tend to possess more drug‐like properties such as high solubility and low promiscuity, and these compounds are more likely to achieve clinical success. Indeed, by enhancing the Fsp 3 values in the course of lead optimization, many research groups succeeded in improving physical properties of candidate compounds …”

Covalent Inhibition in Drug Discovery

“…[79] Recently, Novartis developed FGF401, an aldehyde based covalent inhibitor of FGFR4 which can target a different non-conserved cysteine, Cys 552 of FGFR4. [80]…”