ArticleJournal of medicinal chemistry2021
Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.
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Article in Journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Hidden Interactions: Quantum Perspectives in Drug Design.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Discovery of Rogocekib (CTX-712): A Potent and Selective CLK Inhibitor for Cancer Treatment.ACS medicinal chemistry letters · 2025Article
- Identification of novel compounds with prophylactic activity against hypnozoites using aAntimicrobial agents and chemotherapy · 2025Article
- Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.Cell reports · 2025Article
- CaMKK2: bridging the gap between Ca2+ signaling and energy-sensing.Essays in biochemistry · 2024Review
- How Ligands Interact with the Kinase Hinge.ACS medicinal chemistry letters · 2023Article
- 14-3-3 protein inhibits CaMKK1 by blocking the kinase active site with its last two C-terminal helices.Protein science : a publication of the Protein Society · 2023Article
- Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors.ACS pharmacology & translational science · 2023Article
- SGC-CAMKK2-1: A Chemical Probe for CAMKK2.Cells · 2023Article
- Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses.Journal of medicinal chemistry · 2022Article
- Molecular Mechanisms Underlying CaInternational journal of molecular sciences · 2022Review
- Systemic Ablation ofCells · 2022Article
- Regulation and role of CAMKK2 in prostate cancer.Nature reviews. Urology · 2022Review
- Review
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Authors and funding
24 authors at 5 institutions in 3 countries.
Benjamin J EdufulStructural 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.
Sean N O'ByrneStructural 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.
Louisa TemmeStructural 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.
Christopher R M AsquithStructural 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.ORCID 0000-0001-5871-3458
Yi LiangStructural 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.
Alfredo PicadoStructural 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.
Joseph R PilotteStructural 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.
Mohammad Anwar HossainStructural 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.ORCID 0000-0001-8684-8755
Carrow I WellsStructural 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.ORCID 0000-0003-4799-6792
William J ZuercherStructural 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.
Carolina M C Catta-PretaCentro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.
Priscila Zonzini RamosCentro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.
André de S SantiagoCentro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.
Rafael M CouñagoCentro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil.
Christopher G LangendorfSt Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.
Kévin NaySt Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.
Jonathan S OakhillSt Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.
Thomas L PulliamDepartment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
Chenchu LinDepartment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
Dominik AwadDepartment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.
Timothy M WillsonStructural 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.ORCID 0000-0003-4181-8223
Daniel E FrigoDepartment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States.ORCID 0000-0002-0713-471X
John W ScottSt Vincent's Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.
David H DrewryStructural 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.ORCID 0000-0001-5973-5798
University of North Carolina at Chapel Hill · USThe University of Melbourne · AUUniversidade Estadual de Campinas (UNICAMP) · BRThe University of Texas MD Anderson Cancer Center · USHouston Methodist · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8MTargeting Tumor Microenvironment-Induced Therapy Resistance in Prostate Cancer Bone MetastasisP50CA140388 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI LOGOTHETIS, CHRISTOPHER J., THOMPSON, TIMOTHY CHARLES · 2009 to 2022
$23.4MOverall EvaluationP41GM103403 · NIGMS · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2012 to 2017
$14.3MIlluminating Function of the Understudied Druggable KinomeU24DK116204 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JOHNSON, GARY L. · 2017 to 2022
$13.6MCreation of in vivo active chemical probes for CAMKK2 to treat cancerR01CA218442 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DREWRY, DAVID HAROLD · 2017 to 2019
$2.0MGenetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate CancerR01CA184208 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI FRIGO, DANIEL EDWARD · 2015 to 2019
$1.9MPixel Array Detector for X-ray CrystallographyS10RR029205 · NCRR · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2010 to 2010
$1.8MCharacterization of an understudied kinase, NEK5, in acquisition of a mesenchymaland migratory cell phenotypeR03TR003386 · NCATS · TULANE UNIVERSITY OF LOUISIANA · PI BUROW, MATTHEW E., DREWRY, DAVID HAROLD · 2020 to 2020
$167kNCATS NIH HHS R03 TR003386NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA140388NCI NIH HHS R01 CA184208NCI NIH HHS R01 CA218442NCRR NIH HHS S10 RR029205NIDDK NIH HHS U24 DK116204NIGMS NIH HHS P41 GM103403
Abstract
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
Indexed as
CalciumCalcium-Calmodulin-Dependent Protein Kinase KinaseCalmodulinDose-Response Relationship, DrugHumansMolecular StructureProtein Kinase InhibitorsStructure-Activity RelationshipCalciumCalcium-Calmodulin-Dependent Protein Kinase KinaseCalmodulinCAMKK2 protein, humanProtein Kinase Inhibitors
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