Title: Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes
Authors: Eduful, BJ
O’Byrne, SN
Temme, L
Asquith, CRM
Liang, Y
Picado, A
Pilotte, JR
Hossain, MA
Wells, CI
Zuercher, WJ
Catta-Preta, CMC
Ramos, PZ
Santiago, AD
Counago, RM
Langendorf, CG
Nay, K
Oakhill, JS
Pulliam, TL
Lin, C
Awad, D
Willson, TM
Frigo, DE
Scott, JW
Drewry, DH
Issue Year: 2021
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.
URI: https://publications.svi.edu.au/publications/8396
Other Identifiers 10.1021/acs.jmedchem.0c02274
Publication type Article