Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.

Autor:	Eduful BJ; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., O'Byrne SN; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Temme L; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Asquith CRM; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Liang Y; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Picado A; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Pilotte JR; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Hossain MA; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Wells CI; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Zuercher WJ; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Catta-Preta CMC; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.; Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, São Paulo 13083-886, Brazil., Zonzini Ramos P; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.; Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, São Paulo 13083-886, Brazil., Santiago AS; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.; Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, São Paulo 13083-886, Brazil., Couñago RM; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.; Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, São Paulo 13083-886, Brazil., Langendorf CG; St Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia., Nay K; St Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.; Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia., Oakhill JS; St Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.; Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia., Pulliam TL; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas 77204, United States.; Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, United States., Lin C; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, United States., Awad D; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, United States., Willson TM; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Frigo DE; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas 77204, United States.; Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, United States.; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.; The Methodist Hospital Research Institute, Houston, Texas 77030, United States., Scott JW; St Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.; Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia.; The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville 3052, Australia., Drewry DH; Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; UNC Lineberger Comprehensive Cancer Center, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Aug 12; Vol. 64 (15), pp. 10849-10877. Date of Electronic Publication: 2021 Jul 15.
DOI:	10.1021/acs.jmedchem.0c02274
Abstrakt:	CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency in vitro , while compounds 13g and 45 had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.
Databáze:	MEDLINE
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