The unifying focus of our laboratory's research program is to discover and apply small-molecule tools toward the study of pathogenic transcription in human cancers. We value chemical tools for two reasons. First, the fast action of small molecules – compared to genetic perturbations – allows for detailed study of target protein mechanism of action divorced from confounding secondary effects. Second, the close proximity of chemical tools to starting points in therapeutic science places our efforts in direct relevance to the discovery and development and of new cancer medicines. Therefore, we are pursuing chemical biological approaches within cancer model systems to study the interface of chromatin and cancer biology.
Transcriptional vulnerabilities of cancer cells
Cancer arises from an accumulation of genetic alterations that cooperate to allow uncontrolled cellular proliferation. Alongside these pathogenic alterations is a vast rewiring of transcriptional networks selected to sustain malignant cell growth and survival. Our laboratory is oriented around the hypothesis that dependence on these dysregulated transcriptional programs confers specific cancer subtypes with unique vulnerabilities to the disruption of particular transcriptional regulators. Therefore, we are endeavoring to identify chromatin and transcriptional regulators that are required for survival within a lineage-restricted or molecularly defined cancer context. With an eye toward therapeutic science, we are placing specific emphasis on transcriptional co-regulators with conserved domains or protein functions predicted to be actionable targets for pharmacologic modulation.
Chemical tool discovery
Scripps Research boasts a long tradition of advancing drug discovery and innovating new approaches to translational therapeutic sciences. We are pursuing multiple drug discovery programs with the goal of innovating novel chemical probes for emerging cancer targets. Informed by genetic and chemical biological study of oncogenic transcription programs, we have identified targets including chromatin readers, histone modifiers, and nucleosome remodelers for chemical discovery. Efforts to drug these proteins are empowered by close collaboration with scientists at the California Institute for Biomedical Research (Calibr), a state-of-the-art drug discovery institute and division of Scripps Research. Calibr features world-class small-molecule libraries, automation equipment, and compound management infrastructure, enabling coordinated efforts in discovery chemistry.
Basic biology of pathogenic transcription
In nearly all cancers, dysregulated transcriptional programs accompany malignant transformation. The fundamental goal of our laboratory is to advance a mechanistic understanding of the transcriptional regulatory proteins required for cancer survival or drug resistance. We are accomplishing this by coupling acute chemical perturbations of protein function with integrative transcriptional genomics.
In order to study proteins that lack biologically useful chemical probes, we make frequent use of the dTAG system. This chemical genetic system relies on bifunctional small-molecules to direct FKBP-tagged proteins to the ubiquitin-proteasome system (Erb et al., 2017; Nabet et al., 2018). By placing protein abundance under the control of a small-molecule, we can gain access to phenotypes not observable with slower, genetic perturbations.