Small-molecule drugs that bind to specific target proteins and inhibit their function are a mainstay of precision cancer medicine. The development of therapies to target many proteins known to drive cancer has proven challenging, however, as over 90% of proteins are considered “undruggable” because they lack binding pockets where a small molecule can grab hold. In work funded by an ASPIRE Phase 1 grant from The Mark Foundation, researchers in the laboratory of Daniel Nomura at the University of California, Berkeley used activity-based protein profiling to discover new binding sites on target proteins, as well as covalent ligands that bind those sites. They now aim to expand this work to identify covalent ligands for additional cancer-relevant targets and develop effective cancer therapeutics based on the identified ligands. Molecules that impact target protein function can immediately enter the optimization process for developing a drug. Those that bind the target protein but are functionally ineffective can be converted into proteolysis targeting chimeras (PROTACs) by linking them to chemical structures that are known to recruit their targets to the cell’s protein degradation machinery. The Nomura group will also apply their chemoproteomic approach to expand beyond PROTACs to the discovery and development of a new class of therapeutics called induced proximity-based modalities (IPMs), which bring together proteins to restore normal cellular functions that have gone awry in cells or to create new functions that mitigate disease states. This project has the potential to both lay the foundation for the development of new cancer therapies and introduce new drug discovery paradigms that can be deployed in cancer and other diseases.
Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ, Nomura DK. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat Chem Biol. 2019.
Chung CY, Shin HR, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R, Nomura DK. Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nat Chem Biol. 2019.