ATP-hydrolyzing enzymes like protein kinases are major drug targets for oncology. Drugs that inhibit these enzymes typically engage their ATP-binding (active) sites to inhibit catalysis. However, these active sites are structurally similar to one another, especially in enzymes belonging to the same family, making it difficult to develop drugs that are highly selective with reduced off-target effects.
Ashok Venkitaraman’s laboratory has systematically developed a different approach to this problem – termed ‘allo-targeting’. ‘Allo-targeting’ seeks to create first-in-class drugs that target enzymes outwith their active domains, by modulating regulatory protein interactions or allosteric (regulatory) sites that are unique to that particular enzyme. Over the years, their work has successfully exemplified ‘allo-targeting’ to create novel inhibitors against important anti-cancer targets like the polo-like kinases (PLKs) (Narvaez et al., Cell Chem Biol (2017)) and the BRCA1 E3 ligase (Periasamy et al., Cell Chem Biol (2018)). Their PLK1 inhibitor has been licensed to industry, and is expected to reach human clinical trials in 2022.
Dr. Venkitaraman’ s lab, in collaboration with their colleagues from multi-disciplinary fields at the University of Cambridge, now reports novel inhibitors of the ATP-hydrolyzing DNA repair enzyme, RAD51, that target the regulatory protein-protein interaction between BRCA2 and RAD51 (Scott et al., Cell Chem Biol (2021)), disrupting DNA repair in cells and thereby potentiating DNA-damage-induced cell death. They used a structure-guided approach based on their original structural analysis of the BRCA2-RAD51 complex (Pellegrini et al., Nature (2002)) to create the novel RAD51 inhibitor. This new compound termed CAM833 promises to be of great value not only in dissecting the mechanisms by which DNA repair pathways contribute to genome instability in cancer, but also to seed the future development of anti-cancer drugs that target these pathways.
Dr. Venkitaraman, one of the corresponding authors of this study said,
“My colleagues and I are excited to report our latest progress in creating next-generation inhibitors of enzymes involved in human diseases like cancer via a new approach of targeting the protein-protein interactions that regulate enzyme activity. We believe that this approach, termed ‘allo-targeting’, could lead to new drugs that are more selective and safer than current drugs that bind to the active sites of enzymes.”