The JQ1 experience became a case study in how an openly shared chemical probe can accelerate biology far beyond its original hypothesis. Bradner traces its impact from BRD4 biology to protein degradation, oncogenic transcription factors and therapeutics now in clinical development.
Q3
JQ1 became one of the most widely shared chemical probes in modern biology, yet BET inhibitors have proven difficult to convert into approved medicines. What did that teach you about the distance between a beautiful hypothesis and a drug — and about how openly discovery should be shared?
A:
In this post-genomic era, biomedicine is best practiced by hypothesis-testing. Where available, incisive prototype drugs paired with predictive pre-clinical models can expedite therapeutic translation. The experience of creating, characterizing, studying and sharing the BET bromodomain inhibitor, JQ1, provided a powerful learning. Open access to chemical probes opens up a field of study and accelerates medical progress. In the few years following the publication of JQ1, hundreds of laboratories worked with the molecule to learn about the biology of BRD4 in cancer, heart disease, fibrosis, inflammation, fertility, and most importantly the fundamental role of BRD4 in gene control (transcription elongation). In this way, JQ1 powerfully accelerated scientific discovery, bringing BRD4 biology into view in many disparate fields of study. Years later, scientists have used JQ1 as a work-horse of protein degradation, since our publication of the chemical solution to protein degradation and the molecule dBET1. Others have used JQ1 to recruit BRD4 to oncogenic transcription factors, such as the Androgen Receptor (at Halda, now J&J). JQ1-derived therapeutics are presently in advanced stages of clinical investigation as cancer therapies and for cardiovascular disease. I am hopeful that patients will benefit from the learnings of this remarkable molecule.
