Metalloenzymes represent an important group of clinically validated targets that have been under-targeted by approved therapeutics and inhibitors. These therapeutics or metalloenzyme inhibitors (MEIs) generally consist of two components, a metal-binding pharmacophore (MBP) which reversibly coordinates to active site metal ion(s) and backbone substituents which make non-covalent interactions with peripheral protein residues. A major road block to the development of MEIs has been the overreliance on the same MBP for decades, hydroxamic acid. The Cohen lab has developed a novel approach for developing MEIs by performing fragment-based drug discovery studies around non-hydroxamate MBPs. Unfortunately, these MBPs can be non-druglike due to their utilization of coordinating groups that represent liabilities in drug development, such as carboxylates. To remedy this, we have leveraged bioisostere replacement, which is the replacement of chemical substituents/groups with alternative substituents/groups with broadly similar chemical properties, to develop novel metal-binding isosteres (MBIs). The MBP, picolinic acid (pyridine-2-carboxylic acid) was utilized as a case study in the development of MBIs, as a library of picolinic acid MBIs were synthesized and curated, with many of these compounds being novel ligands for metal coordination and drug development. Using Zn2+ hydrotris(3,5-methylphenylpyrazolyl)borate complexes as a model coordination system of Zn2+ tris-histidine active sites, we demonstrated crystallographically, that MBIs retain the coordinative abilities of the parent fragment. Additionally, MBIs exhibit a broad range of physicochemical properties (pKa, LogP, etc.), with many (~50%) MBIs retaining similar inhibitory activity against a metalloenzyme inhibited by picolinic acid, while not introducing off target inhibitory activity against other metalloenzymes. Efforts to further develop MBIs on alternative heterocyclic scaffolds has been successful, yielding interesting insights into the coordination chemistry of MBPs and MBIs.

Metal-binding pharmacophores utilizing bioisosteres as novel scaffolds for metalloenzyme inhibition

2019 Fall National Meeting

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