AB, University of California, Berkeley
PhD, University of California, San Francisco
I am currently the Director of the Ludwig Small Molecule Discovery (SMD) Program and a Professor of Practice in the Section of Cell and Developmental Biology, Division of Biological Sciences at the University of California, San Diego. Prior to joining Ludwig, I led cross-functional small molecule drug discovery efforts at two biotechnology companies, Tularik (as head of the Orphan Nuclear Receptor Program) and Kalypsys (as Director of Biology). I received my undergraduate degree from UC Berkeley and my PhD from UCSF where I trained as an X-ray crystallographer.
The SMD team and I are focused on making novel small molecule modulators of important cancer targets and pathways and optimizing these compounds to become new oncology therapeutics. Over the past several years, we have developed a highly robust approach for generating high-quality chemical probes and drug candidates. In all of our projects, we complement standard drug discovery techniques with high resolution, imaging-based cellular assays that report on the targeted mechanism. In addition, we employ structure-guided CRISPR/Cas9-genome editing to engineer inhibitor resistance, which allows us to assess on- and off-target activities in cells precisely. Used in combination, these tools have enabled us to develop unprecedented, potent and selective cellularly-active inhibitors. A key example of the success of this approach is centrinone, a highly specific cellular inhibitor of Plk4, a protein kinase essential for centrosome duplication. In collaboration with Ludwig investigators Karen Oegema and Arshad Desai, we have used centrinone to discover key differences in how normal and cancer cells respond to centrosome loss. In particular, we have found that cell lines derived from a devastating pediatric cancer, neuroblastoma, are exquisitely sensitive to centrinone and die soon after treatment.
The SMD Program is pursuing several other similarly mature collaborative drug discovery projects. For example, we have synthesized the first selective, cellularly active small molecule inhibitors of the nuclease FEN1 to exploit synthetic lethal relationships in DNA repair pathways found in ovarian and breast cancers. Finally, we are generating novel small molecule modulators of the BET bromodomain family of epigenetic readers with enhanced efficacy and reduced toxicity for the treatment of hematologic malignancies. For all of our current projects, we are optimizing our inhibitors to improve drug properties and validating our findings in animal models with the goal of generating IND-stage therapeutic candidates in the near future.
Ludwig Institute for Cancer Research, San Diego
9500 Gilman Drive, Cellular and Molecular Medicine East Building
La Jolla, California, U.S.A., 92093-0670
T 858 534 7802