9DI9
Rat branched chain ketoacid dehydrogenase kinase in complex with inhibitor
This is a non-PDB format compatible entry.
Summary for 9DI9
| Entry DOI | 10.2210/pdb9di9/pdb |
| Descriptor | Branched-chain alpha-ketoacid dehydrogenase kinase, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | branch chain ketoacid dehydrogenase, branch chain ketoacid dehydrogenase kinase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 45203.45 |
| Authors | |
| Primary citation | Filipski, K.J.,Martinez-Alsina, L.A.,Reese, M.R.,Evrard, E.,Buzon, L.M.,Cameron, K.O.,Zhang, Y.,Coffman, K.J.,Bradow, J.,Kormos, B.L.,Liu, S.,Knafels, J.D.,Sahasrabudhe, P.V.,Chen, J.,Kalgutkar, A.S.,Bessire, A.J.,Orozco, C.C.,Balesano, A.,Cerny, M.A.,Bollinger, E.,Reyes, A.R.,Laforest, B.,Rosado, A.,Williams, G.,Marshall, M.,Tam Neale, K.,Chen, X.,Hirenallur-Shanthappa, D.,Stansfield, J.C.,Groarke, J.,Qiu, R.,Karas, S.,Roth Flach, R.J.,Esler, W.P. Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948. J.Med.Chem., 68:2466-2482, 2025 Cited by PubMed Abstract: Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing. PubMed: 39560668DOI: 10.1021/acs.jmedchem.4c02230 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.155 Å) |
Structure validation
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