6x4j

Publication Abstract from PubMed

Pantothenate kinase (PANK) is the critical regulator of intracellular levels of coenzyme A and has emerged as an attractive target for treating neurological and metabolic disorders. This report describes the optimization, synthesis, and full structure-activity relationships of a new chemical series of pantothenate competitive PANK inhibitors. Potent drug-like molecules were obtained by optimizing a high throughput screening hit, using lipophilic ligand efficiency (LipE) derived from human PANK3 IC50 values to guide ligand development. X-ray crystal structures of PANK3 with index inhibitors from the optimization were determined to rationalize the emerging structure activity relationships. The analysis revealed a key bidentate hydrogen bonding interaction between pyridazine and R306' as a major contributor to the LipE gain observed in the optimization. A tractable series of PANK3 modulators with nanomolar potency, excellent LipE values, desirable physicochemical properties, and a well-defined structural binding mode was produced from this study.

LipE guided discovery of isopropylphenyl pyridazines as pantothenate kinase modulators.,Sharma LK, Yun MK, Subramanian C, Tangallapally R, Jackowski S, Rock CO, White SW, Lee RE Bioorg Med Chem. 2021 Nov 12;52:116504. doi: 10.1016/j.bmc.2021.116504. PMID:34814071^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.