Genomic profiling of drug-chromatin interactions for accelerated drug development research

The National Center for Advancing Translational Sciences awarded Epicypher, Inc. $1.062 million on September 1, 2026, under the NCATS Project Grant program (CFDA 93.350) to develop Small Molecule Mapper (SMMAP), a genomic profiling platform for mapping interactions between small molecules and chromatin genome-wide.

SMMAP addresses a gap in drug development by providing the first direct method to profile drug-chromatin interactions at scale. Current assays rely on chemical affinity capture or CUT&TAG workflows that lack sensitivity and compatibility with chromatin-associated protein targets. The proposed innovation centers on an immunotethering assay for in situ genomic profiling of small molecule binding, designed to maximize assay sensitivity while maintaining compatibility with transiently interacting targets such as transcription factors. By enabling deeper understanding of a drug's direct molecular targets and downstream responses, SMMAP aims to improve epigenetic drug specificity, reduce development timelines, and accelerate translational research for cancer, inflammation, and neurological disease therapeutics.

Performance occurs in Research Triangle Park, Durham, North Carolina, with a period of performance extending from September 1, 2026, through August 31, 2028. The assistance type is a Project Grant, indicating support for a discrete research project with defined deliverables rather than an ongoing program or center.

Abstract

Gene expression is regulated via the activity of chromatin features such as histone post-translational modifications (hptms) and chromatin-associated proteins (caps). Dysregulation of these chromatin features underlies diverse pathologies including cancer, inflammation, and neurological diseases. Unlike genetic mutations, chromatin (i.e., epigenetic) alterations are dynamic and reversible, making them particularly attractive targets for therapeutic intervention. While significant advances have been made to develop chromatin-targeting therapeutics, progress in bringing epigenetic drugs to the clinic has been slow, often due to poor efficacy and side effects due to low specificity. A deeper understanding of a drug's direct molecular targets and downstream responses is crucial for increasing the likelihood of approval and making the development process more time and cost efficient. While first-generation assays for mapping these interactions exist, they rely on chemical affinity capture or cut & tag-based workflows that lack sensitivity and compatibility with cap targets. Next-generation assays to profile drug-chromatin interactions are needed to unlock new mechanistic insights that will inform drug optimization, improve specificity, and accelerate translational research. To fill this need, epicypher is developing small molecule mapper (smmap), a first-to-market approach to directly map interactions between small molecules and chromatin genome-wide. A key innovation of this proposal is the development of an immunotethering assay for direct genomic profiling of small molecule binding in situ. Smmap includes key steps to maximize assay sensitivity and compatibility. Importantly, unlike recently published cut & tag-based approaches that require high salt washes (precluding their utility to map transiently interacting targets such as transcription factors), smmap maintains high specificity with low-salt washes, enabling mapping of a wide range of targets. Smmap will be transformative for drug development research by providing novel insight into drug mechanism of action, including direct analysis of on-and-off target drug activity and dose response. In phase i equivalent studies, we developed the smmap workflow and demonstrated feasibility for this transformative new approach by generating genome-wide maps for the small molecule inhibitor JQ1, showing the assay can quantitatively detect dose-dependent changes in genome-wide small molecule- chromatin binding interactions. In phase 2, we will develop a robust, rigorously optimized smmap assay kit and assay services for commercial launch. First, we will optimize the smmap workflow to enable mapping of a diverse set of epigenetic drug targets (aim 1). Next, we will develop the application of smmap for analyzing mechanisms underlying drug resistance/sensitivity and target specificity (aim 2). Finally, we will prepare for commercialization by assembling beta kits, performing internal/external validation, and developing automated assay services to enable large-scale clinical / drug development studies (aim 3).