7UE7

PANK3 complex structure with compound PZ-3883

7UE7 の概要

• エントリーDOI: 10.2210/pdb7ue7/pdb
• 分子名称: Pantothenate kinase 3, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: pank, substrate, complex, transferase, pantothenate kinase, inhibitor, activator
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43142.77

構造登録者

White, S.W.,Yun, M.,Lee, R.E. (登録日: 2022-03-21, 公開日: 2023-03-29, 最終更新日: 2024-10-09)

主引用文献

Tangallapally, R.,Subramanian, C.,Yun, M.K.,Edwards, A.,Sharma, L.K.,Yang, L.,Creed, K.,Wang, J.,Jackowski, S.,Rock, C.O.,White, S.W.,Lee, R.E.
Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators.
J.Med.Chem., 67:14432-14442, 2024

PubMed Abstract: Conversion of pantothenate to phosphopantothenate in humans is the first dedicated step in the coenzyme A (CoA) biosynthesis pathway and is mediated by four isoforms of pantothenate kinase. These enzymes are allosterically regulated by acyl-CoA levels, which control the rate of CoA biosynthesis. Small molecule activators of the PANK enzymes that overcome feedback suppression increase CoA levels in cultured cells and animals and have shown great potential for the treatment of pantothenate kinase-associated neurodegeneration and propionic acidemias. In this study, we detail the further optimization of PANK pyridazine activators using structure-guided design and focus on the cellular CoA activation potential, metabolic stability, and solubility as the primary drivers of the structure-activity relationship. These studies led to the prioritization of three late-stage preclinical lead PANK modulators with improved pharmacokinetic profiles and the ability to substantially increase brain CoA levels. Compound (BBP-671) eventually advanced into clinical testing for the treatment of PKAN and propionic acidemia.

PubMed: 39136313
DOI: 10.1021/acs.jmedchem.4c01211

実験手法

X-RAY DIFFRACTION (1.55 Å)