Transcription Factor Drug Discovery

We are developing novel physicochemical routes to drug discovery for transcription factors, which have been less tractable to conventional library screening. In hematopoiesis, transcriptional regulators are widely implicated in homeostasis and pathophysiology, including carcinogenesis. Several hematopoietic malignancies are important childhood diseases: acute lymphoblastic and myeloid leukemias (ALL and AML) are the most and second most common pediatric leukemias, respectively. This work leverages our deep knowledge and technical know-how in protein-DNA biophysics to identify novel search criteria in library screening as well as the preclinical characterization of promising leads. Our drug discovery project complements popular PROTAC-based approaches by offering a credible attempt at direct pharmacologic control of (non-nuclear receptor) transcription factors at their proper site of action: DNA as embodied by genomic chromatin.

Osmotic Biosensing

We are also developing new open-source technology for direct measurement of osmotic pressure in single cells, a critical biophysical parameter that is currently limited to measurement in bulk tissue or inferred indirectly from phenotypes. In addition to impacting the vast literature on cellular osmotic stress response, this technology represents a molecular foundation for enabling in vivo monitoring of physiologic (metabolic) osmotic stress in hematopoietic cell proliferation as well as in disease. In addition to hematopoiesis, the latter encompasses a broad spectrum of inflammatory conditions including diabetes mellitus and its complications, tissue wasting, inflammatory bowel diseases, and sympathetic stress response in cardiovascular diseases.

Molecular Basis of Transcriptional Disorders

The attractiveness of transcription factors to drug discovery and translational science reflects their essential role in regulating gene expression. Indeed, the molecular mechanisms by which transcription factors mediate distinct cellular functions remain among the most fundamental questions in biology. We have significantly contributed to how structure, thermodynamics and conformational dynamics contribute to transcription factor target specificity. In collaboration with external investigators, including clinician-scientists, we are elucidating the molecular biophysics that underpin specific transcriptional disorders. The most recent examples include Waldenström's macro­globulinemia (a B-cell lymphoma), UV- and xenobiotic-induced DNA damage, peripheral tissue fibrosis, and inborn errors of immunity.