Deployment of an AI platform to accelerate transcription factor drug development

About This Grant

Project Summary Transcription factors (TFs) are critical regulators of gene expression, serving as master switches that control cel- lular processes such as development, homeostasis, and response to external stimuli. Dysregulation of TF activity is implicated in a range of diseases, including cancer, fibrosis, and immunological disorders, yet TFs remain an underexploited class of therapeutic targets. Their intrinsic structural complexity, including large multimeric com- plexes and intrinsically disordered regions, has rendered them largely ”undruggable” by traditional approaches. This project seeks to overcome the challenges of targeting TFs by advancing Strategian, an artificial intel- ligence (AI)-powered drug discovery platform built on our proprietary TF-Scan technology. TF-Scan is a high- throughput functional proteomics platform that measures the effects of compounds on TF activity across thou- sands of targets in live cells. Leveraging data from TF-Scan, Strategian uses state-of-the-art machine learn- ing models, including protein and chemistry foundation models, to predict the effects of small molecules on TF- chromatin interactions. In this project, we propose to: (1) Evaluate and optimize cutting-edge protein and compound representations to enhance the predictive performance of Strategian. (2) Discover novel inhibitors for three high-priority TFs using active learning, a method that iteratively improves the AI model by validating its predictions through experimental testing. (3) Develop scalable data infrastructure to support real-time AI-driven drug discovery, including automated data integration pipelines and a web application for internal and external use. The research design integrates functional proteomics, advanced AI methodologies, and scalable cloud in- frastructure to systematically address the challenges of targeting TFs. By iterating through cycles of prediction, experimental validation, and model improvement, Strategian will identify novel TF inhibitors with therapeutic po- tential. The resulting platform will also be deployed to our internal programs, partners, and as a commercial software-as-a-service (SaaS) offering, enabling broad access to TF drug discovery tools. This project aligns with the mission of the National Center for Advancing Translational Sciences (NCATS) by developing innovative tools and approaches to overcome bottlenecks in drug discovery and development. By targeting transcription factors, this work has the potential to open new avenues for treating diseases that are currently intractable, ultimately improving human health and advancing translational science.