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

Author(s):Show less -

Eduful, Benjamin J. ^{[1, 2]} ; O'Byrne, Sean N. ^{[1, 2]} ; Temme, Louisa ^{[1, 2]} ; Asquith, Christopher R. M. ^{[1, 2, 3]} ; Liang, Yi ^{[1, 2]} ; Picado, Alfredo ^{[1, 2]} ; Pilotte, Joseph R. ^{[1, 2]} ; Hossain, Mohammad Anwar ^{[1, 2]} ; Wells, I, Carrow ; Zuercher, William J. ^{[4, 5]} ; Catta-Preta, Carolina M. C. ^{[6, 7]} ; Ramos, Priscila Zonzini ^{[6, 7]} ; Santiago, Andre de S. ^{[6, 7]} ; Counago, Rafael M. ^{[6, 7]} ; Langendorf, Christopher G. ^{[8, 9]} ; Nay, Kevin ^{[8, 9, 10]} ; Oakhill, Jonathan S. ^{[8, 9, 10]} ; Pulliam, Thomas L. ^{[11, 12, 13]} ; Lin, Chenchu ^{[14, 12]} ; Awad, Dominik ^{[14, 12]} ; Willson, Timothy M. ^{[4, 5]} ; Frigo, Daniel E. ^{[15, 11, 12, 13, 16]} ; Scott, John W. ^{[8, 9, 10, 17]} ; Drewry, David H. ^{[4, 5, 18]}

Affiliation:Show less -

^[1] Univ N Carolina, Struct Genom Consortium, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

^[2] Univ N Carolina, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

^[3] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 - USA

^[4] Wells, Carrow, I, Univ N Carolina, Struct Genom Consortium, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

^[5] Wells, Carrow, I, Univ N Carolina, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

^[6] Univ Estadual Campinas, Dept Genet & Evolucao, Inst Biol, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[7] Univ Estadual Campinas UNICAMP, Ctr Quim Med CQMED, Ctr Biol Mol & Engn Genet CBMEG, BR-13083875 Campinas, SP - Brazil

^[8] Univ Melbourne, St Vincents Inst, Fitzroy, Vic 3065 - Australia

^[9] Univ Melbourne, Dept Med, Fitzroy, Vic 3065 - Australia

^[10] Australian Catholic Univ, Mary MacKillop Inst Hlth Res, Melbourne, Vic 3000 - Australia

^[11] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 - USA

^[12] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77054 - USA

^[13] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 - USA

^[14] Univ Texas MD Anderson Canc Ctr, UTHlth Grad Sch Biomed Sci, Houston, TX 77030 - USA

^[15] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 - USA

^[16] Methodist Hosp Res Inst, Houston, TX 77030 - USA

^[17] Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052 - Australia

^[18] Univ N Carolina, UNC Eshelman Sch Pharm, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 - USA

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 64, n. 15, p. 10849-10877, AUG 12 2021.
• Web of Science Citations: 1

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 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. (AU)

• FAPESP's process: 19/14275-8 - Structural analysis of the kinase proteins PRPF4 and DYRK1B, from the CMGC family, and identification of small compound inhibitors
• Grantee: André da Silva Santiago
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
• Grantee: Paulo Arruda
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
• Grantee: Katlin Brauer Massirer
• Support Opportunities: Research Projects - Thematic Grants