Research Projects

This proposal aims to develop therapeutic proteins as efficient catalysts capable of performing chemical transformations under physiological conditions. The focus is on utilizing active site amino acids (such as guanidine, lysine, cysteine, etc.) to catalyze these transformations. We wil design and develop Catalytic Substrates (compounds that undergo chemical transformation when acted upon by protein catalysts). These substrates will be activated in the presence of the protein's active site. Specifically, we will investigate the potential of hydrogen-bonding catalysis, base catalysis, and enamine catalysis mediated by the active site amino acids under physiological conditions. The catalytic substrates will be linked to ligands to guide them to the protein's active site in the complex cellular environment. Examples of proposed substrates include active methylene compounds connected substituted methacrylamides, chloro-substituted acetamides, and sulfamates. These functional groups can facilitate the release of toxins or fluorescent compounds. This approach will be applied to key proteins, such as KRAS, BTK, HSP90, and GLS1. (1) Development of Prodrugs and Fluorogenic Probes for KRAS Mutations: KRAS is associated with several mutations, including KRASG12D, KRASG12V, KRASG12C, KRASG13D, KRASG12R, and KRASG12A, all of which are implicated in cancer. Currently, only two FDA-approved drugs, Sotorasib and Adagrasib, target KRASG12C. We aim to develop a common bifunctional prodrug capable of targeting all KRAS mutations, thus addressing a significant therapeutic gap. (2) Reversible Covalent Prodrugs for HSP90 and BTK: We would like to exploit the Lysine58 of HSP90 and Cysteine 481 of BTK for targeted delivery by designing suitable catalytic substrates. By introducing a carbonyl group capable of enamine formation with lysine 58, with strategically positioned sulfamates, enabling the controlled release of prodrugs. For BTK, we explore substituted chloro acetamides as catalytic substrates.