Many proteins have been identified as targets for drug discovery but are considered ?undruggable? because they lack enzymatic activities. This dogma has eliminated many ideal targets and, thus, it has slowed down progress in fueling discovery of in-vivo chemical probes and potential drugs. Our long-term goal is to develop new approaches to better target the interaction interface of these ?undruggable? proteins. Recently, we developed a novel concept and an automated computational method to identify interfacial hydrophobic core residues that serve as nucleation sites to drive protein dimerization. In preliminary studies, we demonstrate that we have successfully identified and validated a hit compound, LQZ-7, and several active analogues of the hit with two different chemotypes targeting the critical dimerization core residues in the interface of dimeric survivin. In this application, we propose to use medicinal chemistry to further optimize these inhibitors and perform both in-vitro and in-vivo assays to identify lead compounds for further development. To this end, we will accomplish the following specific aims within the funding period: (1) to chemically modify both chemotypes for lead identification and optimization; (2) to analyze newly synthesized analogues using biochemical, biophysical, and cell-based assays; and (3) to determine preclinical pharmacokinetics, toxicity, and in-vivo efficacy of potential lead compounds. The outcome of this study will not only result in potential new in-vivo chemical probes and drugs by directly targeting the dimerization domain of survivin, but also provide evidence for a new approach that can be applied to many other ?undruggable? protein dimers in general, which likely will have a significant and profound impact on future drug discovery process and disease management.
Due to lack of enzymatic activities, many ideal targets such as the homo-dimeric protein, survivin, are considered ?undruggable? and are avoided as target in drug discovery. Recently, we developed a novel concept and an automated computational method that allow us to identify a validated hit, LQZ-7, and several active analogues, which can inhibit survivin by disrupting homo- dimerization. In this application, we will further modify and optimize these compounds to develop potential new in-vivo chemical probes and drugs that directly work on and inhibit survivin for disease management.
