Tan, Li Nomanbhoy, Tyzoon Gurbani, Deepak Patricelli, Matthew Hunter, John Geng, Jiefei Herhaus, Lina Zhang, Jianming Pauls, Eduardo Ham, Youngjin Choi, Hwan Geun Xie, Ting Deng, Xianming Buhrlage, Sara J. Sim, Taebo Cohen, Philip Sapkota, Gopal Westover, Kenneth D. Gray, Nathanael S. 2024-01-20T08:01:35Z 2024-01-20T08:01:35Z 2021-09-05 2015-01-08 0022-2623 https://pubs.kist.re.kr/handle/201004/125874 We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38a (MAPK14) and ABL. Further investigation of the structureactivity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 angstrom cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors. English AMER CHEMICAL SOC RESORCYLIC ACID LACTONE OPTIMIZATION INNATE MODEL Discovery of Type II Inhibitors of TGF beta-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2) Article 10.1021/jm500480k 1 JOURNAL OF MEDICINAL CHEMISTRY, v.58, no.1, pp.183 - 196 JOURNAL OF MEDICINAL CHEMISTRY 58 1 183 196 scie scopus 000347743700011 2-s2.0-84920827062 Chemistry, Medicinal Pharmacology & Pharmacy Article RESORCYLIC ACID LACTONE OPTIMIZATION INNATE MODEL TAK1