Methods and approaches to expand the pharmacological toolset

Project summary Our laboratory identifies small molecules with physiological activity to advance biological discovery and to develop new medicines. The principal goal of this R35 early-stage investigator MIRA proposal will be to enable our research effort collectively, which we believe will be best maximized by focusing on three key areas. In the first, we have been advancing multiple pharmacological approaches in the field of regenerative medicine. Here, we have developed a unique toolset to promote regenerative tissue repair, targeting the Hippo YAP pathway as well as multiple tissue resident stem cell populations. We will continue to augment this toolset, delineating knowledge about the signaling logic of these pathways and identifying key mechanisms that can be potentially exploited therapeutically, as we have done to date. Second, we have significant efforts in ‘liganding’ the roughly twenty transcriptional responses to cellular stress, including heat shock, oxidative, proteostasis, among others. We have developed best in class activators of the NRF2 pathway and have shown superiority to the clinical stage molecule Bardoxolone methyl in animal models. Likewise, we have used chemical tools to understand the essential language of how central carbon metabolism ‘talks’ to the oxidative stress sensing machinery of the cell. We will continue to develop novel small molecules for targeting these largely unliganded transcriptional responses. Lastly, we will continue developing novel methods to effectively mine screening libraries for small molecules with interesting and useful properties. We are developing methods to effectively screen libraries for new covalent reactive groups as well as developing new methodology to screen enzyme families en masse.