A chemical genetics-based approach to biological discovery

Our research group uses the traditional tools of drug discovery--high throughput small molecule screens--coupled with modern target identification techniques to identify new mechanisms and molecules to study and to intervene in the processes causative of human disease. Most projects in the lab start by asking the question whether a drug-like small molecule can be identified to solve a preexisting biological problem by way of interrogating the chemical diversity present in HTS screening libraries (>10^6 molecules). We use chemical proteomics and traditional cell biology-based experiments to retroactively identify and validate the cellular targets and downstream mechanism of action of identified lead molecules (chemical genetics). Our experience suggests this approach frequently results in pharmacologically privileged insight, yielding both the chemical starting points for new drugs and mechanistic information unattainable via classical forward genetics.

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Small molecules for regenerative medicine

Despite perceived organismal complexity, mammals possess relatively poor regenerative potential compared to certain lesser species of Animalia (e.g., amphibians). Indeed, there are many human disease states where an insufficient regenerative response limits organ repair and is determining of disease etiology (e.g., heart failure, T1D, IPF). To overcome these limitations, we have ongoing programs aimed at identifying novel small molecules, drug targets, signaling pathways, and repurposed drugs which control the context-specific cell growth and differentiation pathways limiting regenerative potential in a given tissue or cell type.  To this end, we have completed a number of pathway-centric discovery programs including the identification of small molecules which activate YAP for organ repair and compounds which promote TERT transcription in human cells for longevity-based applications. We have additionally used high content imaging-based screens involving primary cell preparations to identify including molecules which promote regenerative expansion of tissue specific stem cells from alveolar (AEC2s) and intestinal (ISCs) compartments.

Drugging the transcriptional responses to cell stress

The mammalian cell is continually exposed to stresses arising from its environment and its metabolic activities. Nature has therefore selected for a repertoire of sensors and protective transcriptional programs to curb cell death and to restore homeostasis in response to these stimuli. Pharmacological or genetic augmentation of these responses leads to cellular resiliency in various disease states, but only a fraction of stress related transcriptional programs have been drugged or have annotated drug targets. Our current research program aims to identify novel non-toxic molecules and mechanisms for activating stress related transcriptional responses for which pharmacological probes are lacking (e.g., MTF-1 [heavy metal stress], NRF1 [proteasome stress]). Using this approach, we are revealing key information regarding the regulation and ligandability of these pathways and establishing new therapeutic insight into how specific activation of cell stress responses might be used to intervene in a spectrum of human diseases, including chronic kidney disease, neurodegeneration, and autoimmune disorders.

Chemical tools for biological discovery

We complement our drug discovery efforts with an additional focus on developing new high throughput- and molecular diversity-based methods to accelerate the rate and scope of potential biological discovery. To this end, we have ongoing projects related to identifying the cellular binding partners of short ORF encoded peptides (SEPs) and the proteinaceous substrates of various classes of enzymes using photo-crosslinking-based methodologies. We are additionally developing multiplexed technology to profile enzyme-inhibitor interactions en masse to more efficiently screen chemical libraries for new lead inhibitor series. Lastly, we have developed miniaturized assays for interrogating the electrophilicity present in existing chemical libraries to discover new warheads for the development of novel covalent inhibitor templates.