Coenzyme A (CoA) is an essential cofactor involved in many cellular functions such as fatty acid synthesis and regulation, also a crucial component in TCA cycle with its most prominent derivative Acetyl CoA. So understandably any CoA level imbalances in cells results in complications in metabolic regulation of cellular homeostasis. Pantothenate Kinase-Associated Neurodegeneration (PKAN) and Propionic Acidemia (PA) are two such rare diseases where CoA levels are depleted due to either diminished production or sequestration. <i>PanK1-3</i> are responsible for the phosphorylation of pantothenate (vitamin B5) in the rate limiting first step of the CoA biosynthesis pathway. This pathway is regulated with feedback inhibition by AcCoA or PropionlyCoA binding to PanK isoforms and rendering them to inactive conformation. We envisioned to identify a small molecule modulator that activates PanK isoforms and at the same time compete with AcylCoAs interaction. We previously disclosed a small molecule PZ-2891 that allosterically binds to hPanK dimer interface and stabilizes the active confirmation and at the same time making it refractory to AcCoA feedback inhibition. But PZ-2891 has metabolic stability issues limiting its use in pre-clinical evaluation studies. Here in this talk we will present the SAR optimization and our continued efforts in identifying new chemotypes using biophysical screening techniques such as thermal Shift screening, SPR screening and crystallography, that lead us to better molecules with drug like properties.

Small molecule modulators of human pantothenate kinase to mitigate coenzyme-a imbalances for treatment of metabolic disorders

ACS Spring 2022

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