A new vision for the Small Molecule Discovery Center

With major research institutes, funding agencies, and the public eager to see academic research lead to advances in human health, the Small Molecule Discovery Center (SMDC) has tapped a new director to further its mission of combining industrial and academic expertise to advance research programs focused on developing new chemical probes with therapeutic potential.

Charles Hart, PhD, is an adjunct faculty member in the Department of Pharmaceutical Chemistry and director of the Catalyst Program, UCSF’s translational accelerator focused on advancing university discoveries with clinical impact and commercial potential. As the SMDC’s new director, he joins SMDC’s previous director, Department of Pharmaceutical Chemistry Chair Michelle Arkin, in the center’s ongoing collaboration with academics, government labs, and pharmaceutical companies to develop drug leads that address unmet medical needs.

Hart has been fostering academic and industry collaborations, as well as enhanced education in early translational research and entrepreneurship, at both Catalyst and Innovation Ventures, a program dedicated to helping UCSF researchers translate their innovation out of the lab and into the marketplace with greater confidence of success.

“The Catalyst program is both an end user of SMDC results and a potential source of projects for the SMDC,” Arkin said. “Charles has a lot of experience as a biologist in drug discovery companies, and he’s also a very active biologist. His experience and attitude, and his connectivity and engagement with the science community, makes him a great fit for SMDC.”

Arkin, who is now the SMDC’s executive director, said this synergy will propel the center into the future, building on 15 years of success. “Biotech is a huge ecosystem, and [Hart] is definitely an expansion to the ecosystem, bringing a lot of operational experience in transformative partnerships.”

Drug discovery, from bench to bedside

Hart—who holds degrees from UC Berkeley, Stanford University, and Yale University—was responsible for both in vitro and in vivo preclinical translational studies at Threshold Pharmaceuticals for over a dozen years. He brings additional industry experience from Merck KGaA, Galileo Pharmaceuticals, Signature Bioscience, and Affymax.

“I spent 30 years in biotech as a scientist, and I’m relatively new to academia. One of the reasons I’m excited about joining the SMDC is that the projects are all at the cutting edge of modern drug discovery,” Hart said. “The SMDC has remarkable exposure to unique and promising UCSF drug discovery projects.”

In a recent article titled “When to select an academic drug discovery center instead of a contract research organization,” Hart and Arkin articulated the type of collaboration the SMDC will foster, bringing to life a key pillar of the School’s Strategic Plan.

“For a novel target, complex biology, or an unusual mechanism of action, the specific expertise required may be more readily found in the academic setting,” they wrote. “How the project is staffed and managed, and the nature of the information- and data-exchange, are additional important considerations in both the commercial and academic spheres.”

Collaboration and productivity

By building bridges between academic labs and pharmaceutical companies, the SMDC aims to tackle the perception of low productivity that leads to slashed research budgets in the pharmaceutical industry.

“In the old days, drugs were discovered at pharmaceutical companies. And then they were discovered at biotech companies that partnered with pharmaceutical companies,” said Hart. “The SMDC does translational research and also does discovery research, and academia is playing a critical role in modern drug discovery and development––therapeutics, diagnostics, and medical devices.”

Hart said that because the SMDC is focused on nontraditional targets and modalities for pharmacological mechanisms of action, most of the projects tend to be collaborations. The projects, he said, aim for “understanding beyond the eventual [therapeutic] goal, including illuminating the underlying science, and prioritizing the chemical diversity that will be brought to bear on the target.”

Chemical biology and drug discovery

One way Hart hopes to achieve this depth of understanding is through outreach to principal investigators (PIs) that could benefit from the application of chemical biology, which Hart describes as a relatively new discipline around the identification of chemical probes and tools to elucidate biological mechanisms that complement traditional genetic or biochemical approaches.

“I believe there are PIs working on disease mechanisms that might not readily appreciate that their discoveries could be the starting point for targeted drug discovery,” Hart said. “Small molecule probes can have utility as tools both in fundamental, curiosity-driven basic research, and as starting points for drug discovery.”

Both Hart and Arkin identified chemical biology as key to the SMDC’s ongoing discovery of compounds that bind to target proteins in cells, and that can be used to modulate protein and cellular functions.

“What we do day-to-day is chemical biology––developing molecules that perturb biology. And sometimes those molecules will be good enough, and the biology they’re perturbing will be central enough to a disease that those molecules can serve as a starting point for drugs,” Arkin said. “And that is definitely the realm and the responsibility of chemists working in a biological environment—to make molecules that can perturb biology precisely to identify and validate new targets for disease.”