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.

Here we report acrylamide small molecules that form a covalent bond with a conserved cysteine at the TEAD palmitate pocket. Binding studies showed profound stabilization of TEADs by the small molecules, and co-crystal structures reveal that the compounds mimic the binding mode of palmitate. In mammalian cells, the compounds stabilize the TEAD•YAP1 interaction yet reduce TEAD and YAP1 protein levels and inhibit TEAD transcription factor activity.