UCSF researchers join consortium to target cancer in new ways

Scientists from the UCSF School of Pharmacy's Department of Pharmaceutical Chemistry have been selected to lead a new federal initiative aimed at developing new classes of drugs to target cancer.

According to the National Cancer Institute (NCI), "To advance the NCI's mission of bringing novel therapies to patients, and to fully exploit NCI's expertise in the later stage of preclinical development, the Institute is now focusing efforts and resources on drug candidate identification and optimization to enhance the entry of early-stage drug candidates into the NCI therapeutics pipeline."

To accomplish this goal, the NCI is enlisting a nationwide consortium of academic scientists. James Wells, PhD (pictured right), chair of the UCSF School of Pharmacy's Department of Pharmaceutical Chemistry, along with Department of Pharmaceutical Chemistry Adjunct Assistant Professor Michelle Arkin, PhD (pictured left), will lead UCSF's participation in the new NCI initiative, called the Chemical Biology Consortium (CBC). Wells and Arkin are the Director and Associate Director of Biology, respectively, of the Small Molecule Discovery Center (SMDC), which is a laboratory that provides innovative approaches to drug discovery for UCSF researchers. The SMDC will be at the heart of UCSF's consortium work.

Participation in the consortium supports one of the UCSF School of Pharmacy's current strategic goals, which is to create a new framework for drug discovery and development.

New approach

Consortium members will be traveling a different path than that of pharmaceutical firms, which are developing drugs against two major classes of proteins known as kinases and G-coupled proteins. Instead, consortium members will explore a new world of molecular interactions. Their goal is to target—to "drug"—previously untargeted proteins and other molecules. These may include some proteins previously thought to be "undruggable."

Drawing on a range of expertise, the goal of the consortium is to identify new molecular targets that both help tumors survive, grow and spread and for which no drugs have been developed.

UCSF focus

From among competing proposals, SAIC-Frederick—which is the Prime Contractor that manages the operations and technical services at the National Cancer Institute at Frederick, Maryland—selected the UCSF group and its SMDC to serve as a Specialized Applications Center.

The UCSF researchers will use a new, alternative approach, called fragment-based drug discovery in their work. In this approach, drug leads are discovered in pieces and subsequently assembled.

For many targets, conventional high-throughput screening methods yield no likely drug candidates. Wells pioneered the fragment-based method for screening and identifying small molecules—or fragments—that can serve as the starting points for building new drug molecules.

The focus of most drug development has centered on finding molecules that can powerfully gum up the "active" sites of proteins that have been identified as drug targets. Active sites are structures within the protein, often pocket-like, where enzymatic transformation of a bound substrate molecule takes place, driving a particular biochemical event. But fragment-based methods allow researchers to more easily evaluate other surfaces of the protein as potential sites where small molecules can bind and allosterically block the biochemical function of the targeted proteins.

"Our group has extensive experience in oncology drug discovery and has pioneered fragment discovery technologies and their application to difficult undruggable targets," Wells says. In fact, Wells already has focused on using the technique to target caspases, proteins that play a role in cancer, and previously identified small molecules suitable for using as starting points for designing drugs to target caspases.

The SMDC is located at UCSF's Mission Bay campus in Byers Hall, which is the San Francisco home of the multi-site California Institute for Quantitative Biosciences (QB3). QB3 provides key instrumentation in addition to space. While Arkin directs the biology and high-throughput screening efforts in the SMDC, Adam Renslo, PhD, leads the SMDC's medicinal chemistry work.

Multidisciplinary approach

"The challenge of fragment-based drug discovery is that to an extraordinary degree it is really a multidisciplinary operation," Arkin notes. "It requires expertise in protein expression, biophysics, structural biology, computational chemistry and synthetic biology. What's great about UCSF is that we have experts in all of those areas who are interested specifically in fragment-based drug discovery. UCSF's collaborative culture is also critical."

In addition to Wells and Arkin, UCSF members of the NCI consortium include the following scientists who envision the formation of a larger multi-investigator, multi-laboratory Fragment Discovery Center that is organized through the SMDC:

School of Pharmacy

Department of Pharmaceutical Chemistry:

• Thomas James, PhD, structural biology
• Mark Kelly, PhD, structural biology
• Brian Shoichet, PhD, computational chemistry
• Matt Jacobson, PhD, computational chemistry
• Adam Renslo, PhD, medicinal chemistry

School of Medicine

Department of Biochemistry and Biophysics:

• Robert Stroud, PhD, structural biology
• Robert Fletterick, PhD, structural biology

Department of Cellular and Molecular Pharmacology

• Jack Taunton, PhD, medicinal chemistry

In Short

The UCSF School of Pharmacy will lead a UCSF research collaboration, under the National Cancer Institute, to use small molecules to "search" the surface of cells for possible new "druggable" sites. The goal is to develop whole new classes of drugs to target cancer.

Acknowledgement

This project has been funded in whole or in part with Federal Funds from the National Cancer Institute, National Institutes of Health, under SAIC-Frederick, Inc's Prime Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Media inquiries

Kristen Bole
UCSF Pubic Affairs
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