A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

Bioorganic & Medicinal Chemistry
Claudia De FuscoDavid R Spring

Abstract

Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.

Citations

Jan 11, 2019·Organic & Biomolecular Chemistry·Miryam PastorAna Ramos
Jan 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Chunqiong LiRugang Zhong
Feb 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaolan ChenNa Zhang
May 8, 2018·Chemical Science·Jessica IegreDavid R Spring
Mar 7, 2020·Frontiers in Chemistry·Lauro Ribeiro de Souza NetoFloriano Paes Silva
Nov 5, 2019·Trends in Pharmacological Sciences·Georgi K KanevAlbert J Kooistra
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eleanor L AtkinsonDavid R Spring
May 1, 2021·International Journal of Molecular Sciences·Zaira SpinelloSabrina Manni
Dec 21, 2019·Bioorganic & Medicinal Chemistry Letters·Masato TsuyuguchiTakayoshi Kinoshita
May 27, 2021·Organic & Biomolecular Chemistry·Jessica IegreDavid R Spring
Jun 17, 2020·Journal of Medicinal Chemistry·Alexandre BancetIsabelle Krimm
Oct 30, 2020·Journal of Medicinal Chemistry·Paul BrearMarko Hyvönen

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Methods Mentioned

BETA
X-ray
NMR
pulls down
thermal shift

Software Mentioned

Schroedinger
Glide

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