3RWQ

Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)

Summary for 3RWQ

• Entry DOI: 10.2210/pdb3rwq/pdb
• Related: 3RWP 3SC1
• Descriptor: 3-phosphoinositide-dependent protein kinase 1, [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[2-(pyridin-3-yl)ethyl]amino}pyrazin-2-yl)methanone, GLYCEROL, ... (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: 36906.91

Authors

Kazmirski, S.,Kohls, D. (deposition date: 2011-05-09, release date: 2011-11-16, Last modification date: 2024-10-09)

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

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: 22040023
DOI: 10.1021/jm201019k

Experimental method

X-RAY DIFFRACTION (2.55 Å)