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.

Grant Number: 5R35GM146865-04
NIH Institute/Center: NIH
Principal Investigator: Michael Bollong