7UE3
PANK3 complex structure with compound PZ-3804
Summary for 7UE3
| Entry DOI | 10.2210/pdb7ue3/pdb |
| Descriptor | Pantothenate kinase 3, 6-[4-({4-[(2R)-1-hydroxypropan-2-yl]phenyl}acetyl)piperazin-1-yl]pyridazine-3-carbonitrile, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (6 entities in total) |
| Functional Keywords | pank, substrate, complex, transferase, pantothenate kinase, inhibitor, activator |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43986.66 |
| Authors | White, S.W.,Yun, M.,Lee, R.E. (deposition date: 2022-03-21, release date: 2023-03-29, Last modification date: 2024-10-09) |
| Primary citation | 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 Cited by 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: 39136313DOI: 10.1021/acs.jmedchem.4c01211 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.56 Å) |
Structure validation
Download full validation report
