Preventing kinases from phosphorylating their targets is one of the most common strategies for targeted cancer therapy. Amit Choudhary, chemical biologist at Harvard Medical School, Brigham and Women’s Hospital, and the Broad Institute, is exploring whether the enhancement of phosphorylation could also be an effective mechanism of action for anti-cancer drugs. Toward that goal, Choudhary and his team are developing a new class of compounds that bring together kinases with selected target proteins to induce aberrant phosphorylation events. Choudhary hypothesizes that these neo-phosphorylation events could trigger an immune response, leading to cancer cell death. His strategy relies on the principle of chemically induced proximity, in which a small molecule is used to bring two cellular proteins together to artificially modulate biological processes such as phosphorylation. The new class of small molecules, termed Phosphorylation-Inducing Chimeric Small molecules (PHICS), will be formed by joining a small molecule kinase binder with a small molecule binder of the target protein. The team has selected a short list of high-value cancer targets with diverse properties as test cases for this new class of compounds. By designing PHICS to induce phosphorylation on these cancer targets, Choudhary hopes to determine whether an immune response can be evoked that could potentially enhance control of tumors by the immune system.
Siriwardena SU, Munkanatta Godage DNP, Shoba VM, Lai S, Shi M, Wu P, Chaudhary SK, Schreiber SL, Choudhary A. Phosphorylation-Inducing Chimeric Small Molecules. J Am Chem Soc. 2020.
Pergu R, Shoba VM, Chaudhary SK, Munkanatta Godage DNP, Deb A, Singha S, Dhawa U, Singh P, Anokhina V, Singh S, Siriwardena SU, Choudhary A. Development and Applications of Chimera Platforms for Tyrosine Phosphorylation. ACS Cent Sci. 2023.