Month: March 2021

Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study

Eleanor L. Atkinson, Jessica Iegre, Paul D. Brear, Elizabeth A. Zhabina, Marko Hyvönen and David R. Spring

Molecules 26(7):1977(2021)
DOI: 10.3390/molecules26071977
Pubmed: 33807474


Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. Continue reading →

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Chemical probes targeting the kinase CK2: a journey outside the catalytic box

Jessica Iegre, Eleanor L. Atkinson, Paul D. Brear, Bethany M. Cooper, Marko Hyvönen and David R. Spring

Organic & Biomolecular Chemistry, in press, (2021)
DOI: 10.1039/D1OB00257K


CK2 is a protein kinase that plays important roles in many physio-pathological cellular processes. As such, the development of chemical probes for CK2 has received increasing attention in the past decade with more than 40 lead compounds developed. In this review, we aim to provide the reader with a comprehensive overview of the chemical probes acting outside the highly-conserved ATP-site developed to date. Continue reading →

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A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

Duncan E. Scott, Nicola J. Francis-Newton, May E. Marsh, Anthony G. Coyne, Gerhard Fischer, Tommaso Moschetti, Andrew R. Bayly, Timothy D. Sharpe, Kalina T. Haas, Lorraine Barber, Chiara R. Valenzano, Rajavel Srinivasan, David J. Huggins, Miyoung Lee, Amy Emery, Bryn Hardwick, Matthias Ehebauer, Claudio Dagostin, Alessandro Esposito, Luca Pellegrini, Trevor Perrior, Grahame McKenzie, Tom L. Blundell, Marko Hyvönen, John Skidmore, Ashok R. Venkitaraman, Chris Abell

Cell Chemical Biology, Online now , (2021)
DOI: j.chembiol.2021.02.006
Pubmed: 33662256
PDB coordinates:
6TV3 (3D view), 6TWR (3D view), 6TW4 (3D view), 6XTW (3D view), 6TW9 (3D view)

Lay Summary

BRCA2 is a protein that helps the body fix broken DNA. It makes sure RAD51, works when the cell needs to fix broken DNA. Scientists made a new drug candidate, CAM833,  that stops BRCA2 and RAD51 from working together. It can stop cancer cells from growing, especially when used together with other chemicals.


BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. Continue reading →

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