Chemical Biology
We use proximity-inducing small molecules with appropriate dosing and timing to leverage their fast action and specificity to target protein mechanisms compared to other genetic perturbations. The small molecule can be used as a tool to pursue a detailed study of the target protein's mechanism, divorced from secondary effects. Our lab uses small molecules with absolute genetic specificity, along with other chemical genetic tools, to study epigenetic processes.
Chemical Genetic Tools to Dissect Functional Interplay of PAX3-FOXO1 and CBP/P300
Using chemical genetic tools, we demonstrated that the fusion oncoprotein PAX3FOXO1 (P3F), the key oncogenic driver of fusion-positive rhabdomyosarcoma (FP-RMS), recruits CBP/p300 and is dependent on CBP/p300 for its transcriptional activity. Pharmacological inhibition or degradation of CBP/p300 disrupts P3F function, leading to selective cell death in FP-RMS cell lines.
Development of chemical proximity inducers for Fusion Oncoproteins
We aim to develop a Proteolysis-Targeting Chimera (PROTAC) to degrade the fusion oncoprotein PAX3-FOXO1 and the transcription factor RUNX2. We will use this degrader as a chemical tool, in combination with other genetic tools, to understand the epigenetic mechanisms underlying PAX3-FOXO1 and RUNX2 and to develop cancer therapies that achieve clinical success against rhabdomyosarcoma. Also, we develop chemical tools to induce the proximity of target proteins with epigenetic modulators. We recently successfully acetylated the androgen receptor (AR) by bringing a histone acetyltransferase in proximity to the AR using a bifunctional molecule.
Developement of Biocatalyst-controlled Epigenome Editing Tools
Small-molecule chemical probes are crucial for precisely and quickly understanding epigenetic mechanisms. I am developing a bifunctional molecule comprising a biocatalyst and a protein ligand that will bind to the d-Cas integrated protein system to precisely acetylate target proteins, including histones, thereby expressing the specific gene of interest in a precise and temporal manner.
Developing Phenotypic High-Throughput Screening Platform to Develop Lead for Epigenetic Modulators
Despite increased demand for new chemical probes as inhibitors and degraders of epigenetic modifiers, lead development for inhibitors and degraders is slow. We are building high-throughput screening platforms on 384-well plates to discover rapidly and automatically new chemical probes and leads for transcription factors and epigenetic modulators, .
