Native regulome profiling captures the complete landscape of chromatin-associated proteins in their natural context, quantifying transcription factors (TFs), cofactors, and chromatin machinery that regulate gene expression. Integrating these proteomic measurements with chemical perturbations and AI-driven modeling reveals how compounds reshape regulatory networks. This systems-level approach enables machine learning–guided discovery of small molecules that functionally modulate TF activity, unlocking new therapeutic opportunities across the previously “undruggable” regulome.

The cellular integrated stress response (ISR) enables cells to adapt to stressors and return to homeostasis. However, unresolved chronic ISR activation leads to cellular apoptosis and is a hallmark of several neurodegenerative diseases. The ISR pathway signals through transcription factors ATF4, CHOP, GADD34, and ATF5, which determine cellular fate. Here, I will describe the discovery and development of RTX-117, an oral, brain-penetrant inhibitor of the ISR currently entering Phase 1 clinical trials. 

The p300-selective degrader candidate of represents a novel therapeutic strategy targeting epigenetic regulation in cancer. By selectively degrading the histone acetyltransferase p300, our molecule disrupts oncogenic transcriptional programs while sparing CBP, minimizing off-target effects like thrombocytopenea. Preclinical studies demonstrate potent antiproliferative activity in p300-dependent malignancies, including hematologic and solid tumors. The degrader exhibits favorable pharmacokinetics suitable for oral administration. Its mechanism of action offers a promising avenue for precision oncology, particularly in cancers with p300 over expression or dependency (e.g., CBP mutation). Ongoing optimization aims to enhance selectivity, bioavailability, and clinical translation potential.

We describe efforts to optimize small-molecule NRF2 modulators that disrupt the interaction between NRF2 and the Kelch domain of KEAP1. Structure-guided design and SAR studies have led to improved potency and selectivity, enhancing NRF2 stabilization and downstream antioxidant responses. This work supports the development of therapeutics targeting oxidative stress-related diseases by modulating the KEAP1–NRF2 axis.

Pancreatic ductal adenocarcinomas (PDAC) resist KRAS inhibitors by shifting to OXPHOS-dependent metabolism. Here, we identify the transcription factor ZBTB11 as a key driver of this metabolic reprogramming. We also develop molecular glues that induce ZBTB11 degradation and resensitize PDAC cells to KRAS inhibition. This approach selectively targets resistant cancer cells while sparing healthy neurons, establishing ZBTB11 as a druggable therapeutic vulnerability.