Translating novel cancer targets and mechanisms from the CTD^2 Network using molecular glues

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PROJECT SUMMARY Our current CTD2 Network Center discovered that many cancers, following drug treatment, emerge in a stable cell state resistant to apoptosis and vulnerable to ferroptosis. While pursuing efforts to translate these findings, and the findings of other discoveries throughout the Network, we recognized a central need for the CTD2 Network to adapt new methods of drug discovery. Here, we describe computational and experimental advances in the discovery of small-molecule binders and molecular glues emerging from the novel use of synthetic organic chemistry, DNA barcoding, computational analyses of enriched barcodes following affinity-based screens, and chemical biology assays. We base our strategy on the discovery that small-molecule glues can bring together two proteins that do not otherwise associate. We will exploit DNA-barcoded compounds to discover drug-like molecular glues that are: 1) degradation-selective, 2) tissue-selective, and 3) oncogene-selective. This proposal aims to develop novel methods to translate CTD2 Network discoveries of difficult-to-drug cancer vulnerabilities towards novel therapeutics. The methods yield molecular glues that confer activities not available by current drug-discovery methods, and to develop a blueprint to discover systematically degraders for cancer vulnerabilities, tissue-restricted enzyme inhibitors, and compounds that restore protein–protein associations impaired by oncogenic mutation. In Aim 1, we will develop novel capabilities to identify specific presenter proteins and to discover molecular glues. In Aim 2, we will discover novel molecular glues using DNA-barcoding technology. In Aim 3, we will determine mechanism of action in vitro and in cells and engage CTD2 Network Centers to complement our chemical biology expertise. These compounds will serve as launching pads to inform cancer vulnerabilities and, upon chemical optimization, therapeutic hypotheses in specific cancer types. Successful outcomes of this project include the identification of new chemical matter to target important genetic targets in cancer, establishment of a novel and powerful resource available to the CTD2 Network, and potentially a new paradigm for drug discovery.