3RWP
Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)
Summary for 3RWP
| Entry DOI | 10.2210/pdb3rwp/pdb |
| Related | 3RWQ 3SC1 |
| Descriptor | 3-phosphoinositide-dependent protein kinase 1, GLYCEROL, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | kinase domain, transferase, phosphoserine: sep, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: O15530 |
| Total number of polymer chains | 1 |
| Total formula weight | 37018.09 |
| Authors | Greasley, S.E.,Hickey, M.,Ferre, R.-A.,Krauss, M.,Cronin, C. (deposition date: 2011-05-09, release date: 2011-11-16, Last modification date: 2024-10-16) |
| Primary citation | Murphy, S.T.,Alton, G.,Bailey, S.,Baxi, S.M.,Burke, B.J.,Chappie, T.A.,Ermolieff, J.,Ferre, R.,Greasley, S.,Hickey, M.,Humphrey, J.,Kablaoui, N.,Kath, J.,Kazmirski, S.,Kraus, M.,Kupchinsky, S.,Li, J.,Lingardo, L.,Marx, M.A.,Richter, D.,Tanis, S.P.,Tran, K.,Vernier, W.,Xie, Z.,Yin, M.J.,Yu, X.H. Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1). J.Med.Chem., 54:8490-8500, 2011 Cited by PubMed Abstract: Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines. PubMed: 22040023DOI: 10.1021/jm201019k PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.92 Å) |
Structure validation
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