A Chemoproteomic Approach to Identify Molecular Glues for Targeted Cancer Therapy - Project Summary / Abstract Research Plan: Targeted protein degradation using molecular glues - small molecules that bring a protein of interest in proximity to an E3 ligase - emerged as a promising therapeutic strategy for cancer, especially for proteins that have been historically challenging to target with conventional drug discovery approaches. However, the development of molecular glue degraders presents a formidable challenge due to the absence of a systematic methodology for identifying these compounds. Currently, most molecular glue degraders employed in the clinic setting have been identified through serendipitous discovery, thereby limiting their potential applications for targeting intractable oncogenic proteins. To address this challenge, I have developed a novel chemoproteomic approach, referred to as Lysate IP , which enables the identification of novel molecular glue activities in small molecules. In my preliminary investigation using this method, I discovered that lenalidomide, an FDA-approved molecular glue degrader, induces ASS1 recruitment to CRBN, but it does not result in ASS1 degradation. Given the extensive use of lenalidomide in the clinic and in CRBN-based PROTACs, it is crucial to examine all potential activities that lenalidomide elicits. Therefore, during the mentored K99 phase, I propose to investigate the implication of ASS1 recruitment to CRBN by lenalidomide, and its role in lenalidomide resistance in multiple myeloma (Aim 1). In the subsequent independent R00 phase, I intend to utilize the developed Lysate IP assay for the large-scale, multiplexed identification of novel molecular glues against unexplored E3 ubiquitin ligases (Aim 2), as part of the anticancer drug discovery process. The primary objective of this research is to systematically identify and characterize new molecular glues with the ultimate goal of expanding the small molecule toolbox for targeted cancer therapy. Career Development Plan: I have created a 5-year career development plan that enables me to attain my goal of becoming an independent investigator in cancer biology. My extensive background in chemical biology and medicinal chemistry has positioned me in a unique position to accomplish the goals outlined in this proposal. Supported by an interdisciplinary team of advisors and collaborators, including Drs. Benjamin Ebert, Eric Fischer, Scott Armstrong, and Amit Choudhary, I aim to acquire novel proficiencies in a range of areas including large- scale chemical screenings, mass spectrometry, omics-scale data analysis and visualization, and comprehensive cancer biology. Additionally, with institutional support from the Broad Institute, as well as through formal coursework and training, I will establish an independent, cancer-oriented drug discovery program with the goal of expanding the range of druggable proteins using small molecules.
