Case-study in consortium-based drug discovery: allosteric inhibition of the AAA ATPase p97

Recorded On: 02/06/2017

There has been a significant effort over the past decade to bring drug discovery to academia, but this comes with many challenges to balance the potential advantages. In academia, the focus on innovative technologies and novel biological targets encourages us to work on difficult or commercially underpowered problems in healthcare, but how do we develop a strong team with diverse expertise from relatively small and loosely affiliated academic labs? At the UCSF Small Molecule Discovery Center, we have taken various approaches to this challenge, including working with drug discovery consortia. The National Cancer Institute's (NCI's) Chemical Biology Consortium is a consortium of academic, government, and private-sector laboratories working together to find innovative treatments for cancer. Through this consortium, a team of scientists from Caltech, University of Pittsburg, UCLA, University of Minnesota, SRI International, NCI, and UCSF have developed novel inhibitors of the AAA ATPase p97, an exciting, emerging target in cancer. p97 is a master regulator of protein homeostasis, and modulates ubiquitin-dependent degradation as well as membrane fusion activities throughout the cell. These events are directed by a network of protein-protein interactions and ATPase-dependent changes in p97 conformation. The team has designed allosteric and PPI modulators for different aspects of this complex machine and has solved the first high-resolution structures of p97 bound to an inhibitor using cryo-electron microscopy (cryo-EM). We see cryo-EM as a cutting edge technology for structure-guided design in drug discovery. By comparing inhibitors of p97 that act through different mechanisms, we aim to develop new experimental therapeutics and to decipher the complex biological pathways regulated by p97 activity.

Dr. Michelle Arkin

Associate Professor, Pharmaceutical Chemistry; Director, Biology, Small Molecule Discovery Center

University of California, San Francisco, CA

Michelle Arkin is an Associate Professor of Pharmaceutical Chemistry and the Director of Biology at the Small Molecule Discovery Center at UCSF. The Small Molecule Discovery Center is a research ‘colaboratory’ that works with academic and biotech investigators to develop small-molecule probes and drug leads. Michelle’s research is focused on structure/function and chemical biology of allosterically regulated enzymes and protein-protein interactions (PPI). Her lab also has a strong interest in developing probes and drug leads to address mechanisms of neurodegeneration, cancer, and parasitic disease. Michelle is involved in academic drug discovery as an investigator in the NCI’s Chemical Biology Consortium and the Tau Consortium, an editor of the NIH’s Assay Guidance Manual, and a board member of the Academic Drug Discovery Consortium.

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