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Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors |
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| Authors: | Mark A Seefeld Meagan B Rouse Kenneth C McNulty Lihui Sun Jizhou Wang Dennis S Yamashita Juan I Luengo ShuYun Zhang Elisabeth A Minthorn Nestor O Concha Dirk A Heerding |
| Institution: | 1. Oncology Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA;2. Oncology Biology, GlaxoSmithKline, Collegeville, PA 19426, USA;3. Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA 19426, USA;4. Computational, Analytical and Structural Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA |
| Abstract: | A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β. |
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