Talus Bioscience Inc

Activity-based Regulome Profiling for the Discovery of Covalent Transcription Factor Inhibitors - Research Summary the Human Genome Encodes More Than 1,600 Transcription Factors (TFS), Along With Additional Cofactors, Chromatin Regulators, and Structural Proteins That Collectively Execute the Regulatory Instructions Encoded Within the Nuclear Dna. Dysfunctions of These Proteins Are Known to Drive Multiple Diseases Such as Cancer, Inflammation-related, and Neurological Conditions. in Cancer, These Proteins Are Frequently Amplified or Overexpressed to Drive a Gene Expression Program That Facilitates the Initiation and Progression of Various Types of Leukemia, Sarcoma and Other Tumors. Despite the Importance of These Proteins, TFS Have Been Considered Undruggable Due to Challenges in Modeling Their Activity in Vitro. We Have Solved These Shortcomings by Implementing an In-cell Functional Proteomics Drug Discovery Platform That Quantifies the Effects of Small-molecules on the Abundance of TF Bound to the Genome in a Diversity of Cell and Tissue Types. the Platform Is Based on Chromatin Extraction by Salt Separation, Coupled to Data Independent Analysis Mass Spectrometry (chess-dia), Which Was Recently Reported. in This Proposal, We Adapt This Technology to Enable the Discovery of Covalent Small Molecule Inhibitors, a Type of Chemistry That Has Recently Enabled Targeting of the Previously Undruggable Kras Protein. First, We Will Compare the Efficacy of Several Different Covalent Screening Approaches in Combination With Chess-dia Proteome Analysis, Determining Which Strategy Is Best for Compound Discovery. Computational Tools Will Also Be Built to Robustly Identify Functional Covalent Hit Compounds, and to Identify the Compound:protein Adducts That Are Formed Upon Compound Binding. Several Well-characterized Covalent Inhibitors Will Be Used to Validate the Accuracy of These Methods. With a Validated Covalent Screening TF Assay, We Will Then Optimize a Secondary Assay Using Intact Protein to Verify That Hit Compounds Can Label Target Proteins in a Stoichiometric, Specific Way. With These Tools in Hand, We Will Then Perform a Pilot Screen to Prove the Assay’s Utility in a Discovery Setting, Using a Subset of a Commercial Covalent Compound Library. These Compounds Contain a Diverse Array of Reactive Warheads, and This Will Allow Us to Understand Various Performance Metrics of the Optimized Assay. This Data Package Will Enable Us to Perform Full-scale Internal Screens for Compounds That Target Talus’ TFS of Interest, as Well as Provide the Foundation for Business Development Discussions With Biotech and Pharmaceutical Companies Interested in TF Inhibition.