Bromodomains

 

Encoded in the genomes of all human cells, is the ability to undergo cell division. This process requires a symphony of growth genes to be activated. The activation of the growth program in healthy cells, as during development of a child or with the ongoing production of blood cells, is conducted by a small number of master regulatory genes called transcription factors. Encoded in the genomes of all cancer cells, is an abnormal addiction to unrestricted cell growth that is principally mediated by an oncogenic transcription factor called MYC.  We hypothesized that MYC functions collaboratively with cellular memory proteins, called bromodomains.  To target cancer cell memory and MYC-dependent cancer growth signaling, we developed first bromodomain inhibitors for the BET family and its prototypical member BRD4. Using our prototypical molecule, JQ1 (Nature, 2010) we have validated BRD4 as a cancer therapeutic target in solid and hematologic cancers.  Ongoing research in the group uses a similar chemical biological strategy to study the expanded bromodomain family in biology and disease.

Enhancers

Every human cell possesses the same set of roughly 20,000 genes.  The highly specific shapes and functions of individual human cells are accomplished by tight regulated control of gene activation and repression.  Gene activation is regulated by nearby genomic sequences that function as cell type specific switches, so-called “enhancers”.  In cancer, the genes encoded for growth and survival are locked in an “on” state by MYC, as above, and other oncogenic gene regulatory proteins.  With a mechanistic curiosity and a therapeutic ambition, we have become interested in understanding enhancer networks and drugging enhancer factors.  Collaborative from our group discovered that BET bromodomains are enhancer factors (Cell, 2011) that localize to massive on-switches in cancer cells called Super Enhancers (Cancer Cell and Cell, 2013).  We anticipate that the detailed study of enhancers in cancer will lead to new diagnostic and therapeutic insights.

Therapeutics

We expect that the new chemical technologies and mechanistic insights realized in our laboratory can create or guide new medicines.  This research often requires optimization of prototype chemical probes to drug-like clinical candidates, an interest of our group.  Different from conventional industrial approaches to drug discovery, our laboratory divorces the science of therapeutics from commercial considerations and works to exemplify an open-source approach to early stage drug discovery.  Chemical tools from our group are openly provided for research in real-time, free of charge and without restriction or requirement for reporting results – though we welcome an opportunity to make collaborative contributions.  Already, more than 450 laboratories worldwide utilize chemical probes from our lab.  For definitive cancer drug development, we collaborate with like-minded experts typically through start-up biopharmaceutical companies. To date, four first-in-class therapeutic technologies from our research have translated to human Phase I and II clinical trials: BET bromodomain inhibition (TEN-010; Tensha Therapeutics), HDAC6 inhibition (Rocilinostat, ACY-241; Acetylon Pharmaceuticals), and soft-drug HDAC inhibition (SHP-141; SHAPE Therapeutics | TetraLogic).  Additional technologies to study and disrupt enhancers have been licensed to Syros Pharmaceuticals.