Small-Molecule Probes of Biological Processes
My group uses asymmetric organic synthesis and a novel strategy for the synthesis of small-molecule probes—a strategy that is inspired by modular biosynthetic pathways that yield naturally occurring small molecules. We next develop assays using intact cells, in some cases primary cells (e.g., β cells from human pancreata; leukemic stem cells from mouse bone marrow), that enable the identification of selective probes. We then exploit the modular synthetic routes to optimize potency and selectivity features of the compounds identified in the assays. Using this approach, we have reported over the past three years the discovery and use of novel small-molecule probes of a variety of challenging targets, including (1) the histone methyltransferase G9a, (2) Jumonji C domain–containing histone demethylases, and (3) the Keap1-Nrf2 interaction in oxidative stress signaling. During this time, we also identified small-molecule probes of critical disease pathways, including (1) cytokine-induced β-cell apoptosis in diabetes, (2) neuregulin-ErbB4 signaling in neurological disease, and (3) cancer stem cells in breast cancer.
We are using small molecules as tools to uncover targets that are not altered in tumors but that have been co-opted in the context of the cancer to perform a critical role. For instance, we have searched for small molecules that induce polyploidization and cancer cell differentiation in the context of acute megakaryoblastic leukemia, a cancer characterized by a block in differentiation. Exploring the mechanism of a small-molecule inducer of polyploidization led to the description of a role for the kinase Aurora A in this process. We have a particular focus on exploring the roles of chromatin-modifying enzymes or associated proteins in regulating gene expression and maintaining cell state in cancer. In studying leukemia cells that harbor mutations in the H3 K36 methyltransferase NSD2, we have used a novel HDAC1/2-selective small-molecule inhibitor to uncover a dependency on these histone deacetylase isoforms, which intriguingly are found in cells as a stable ternary complex (NSD2-HDAC1-HDAC2).
Cancer Genetic and Lineage Features That Confer Sensitivity to Small Molecules
We expanded the approach above by creating the Cancer Therapeutics Response Portal (www.broadinstitute.org/ctrp) to enable the research community to correlate genetic features to small-molecule sensitivities in individual lineages, while controlling for confounding factors of cancer cell-line profiling. Mining these data, we have uncovered a number of previously undescribed candidate dependencies, including associating activating mutations in the oncogene β-catenin with sensitivity to navitoclax, an antagonist of the prosurvival protein BCL-xL. The resource continues to be used to develop novel therapeutic hypotheses and to accelerate the discovery of drugs matched to patients by their cancer genotype and lineage.
Anti-infective Targets in Microbes
We are pursuing the hypothesis that new types of chemicals, accessed through advances in synthetic chemistry, may afford alternative approaches for targeting microbes. Starting with assays using intact cells, we have identified small molecules that selectively and potently kill infectious agents, including, among others, Trypanosoma cruzi, Plasmodium falciparum, and Mycobacterium tuberculosis, the causative agents of Chagas disease, malaria, and tuberculosis, respectively. By exploring how these small molecules act, for instance by sequencing drug-resistant strains, we are uncovering targets not otherwise known to be critical for the growth of these microbes. We then are using these probes to explore the roles of these targets in the context of infectious disease.
Grants from the National Cancer Institute, the Bill and Melinda Gates Foundation, and the National Institute of General Medical Sciences provided partial support for the work on cancer, infectious diseases, and the science of therapeutics, respectively.
As of February 22, 2016