Our lab synthesizes small molecules that can be used to better understand the biology of disease and ultimately to produce more effective therapeutics.
In the UC San Francisco lab of Adam Renslo, PhD, scientists synthesize small organic molecules that can be used to better understand the biology of disease and ultimately to produce more effective therapeutics. “Small” molecules made up of about 25 to 75 atoms comprise the active ingredients of the majority of drugs used to treat human disease. The reason small molecules are so effective is that they are the correct size to interact with the enzymes and receptors that mediate biological processes, including disease.
An effective drug must possess a variety of favorable properties, including:
- Sufficient potency to exert the desired effect at a tolerable dose
- Selectivity for the desired biological target(s) over the multitude of other “off-targets” present in a complex organism
- Sufficient stability and persistence in the body so that the drug can reach its intended target
The medicinal chemist seeks to solve this multifactorial problem by synthesizing candidate drug molecules, so-called drug “leads,” and evaluating these in the test tube and eventually in animals. The process is iterative and empirical, with each experimental result informing the design of improved leads, ultimately producing specific compounds that can be evaluated in human clinical trials.
To advance the field of medicinal chemistry, our research group is employing fragment-based lead discovery to identify drug leads for new classes of biological targets such as protein-protein interfaces and allosteric sites on enzymes. We are pursuing this work in collaboration with other UC San Francisco labs (Arkin, Fletterick, Jacobson, James, Wells) that together constitute a Fragment Discovery Center. We are also developing new chemical technologies to more effectively deliver therapeutics to their intended sites of action. As chemical biologists, we employ novel chemical probes to better understand biological pathways and the molecular pharmacology of small molecule therapeutics. These probes can be designed de novo based on known biological substrates or by searching large collections of small molecules for those with the desired properties (small molecule screening). In summary, our current projects fall into four general areas:
- Targeted drug delivery – invention of new prodrug technologies for selective drug release in chemical environments associated with disease pathology.
- Chemical probes – fluorescent probes and activity-based probes for the interrogation of biological pathways and drug pharmacology.
- Fragment-based lead discovery – application of fragment screening and chemical optimization to challenging drug discovery problems.
- Peptidomimetics – design and use of novel amino acids to improve the properties of peptides as therapeutics.
Advances in genetic sequencing and computational and systems biology mean that a multitude of new biological targets and pathways are being discovered and their functions revealed. In particular, the importance of protein-protein interactions in modulating enzymatic activities and thereby regulating biological pathways is becoming increasingly evident.
Many of these discoveries about new biological targets and pathways are being made at UCSF by world-class researchers in systems and molecular biology. This deluge of new information has enormous potential to be translated into advances in treating human disease, if effective drugs can be identified for these novel targets.
However, whereas the vast majority of existing drugs target enzymes or receptors that naturally bind small molecules (e.g., G-protein-coupled receptors and kinases), finding small molecules that bind to protein-protein interfaces is a major challenge that remains very much a research problem. UCSF has a thriving research enterprise in the small molecule arena and is home to the Small Molecule Discovery Center, for which Renslo serves as associate director.
Thus, the confluence of new biological knowledge and a clear need for new approaches in small molecule discovery make UCSF an ideal place in which to pursue our research. As well, scientists in systems and molecular biology and small molecule discovery are physically located on the same UCSF research campus at Mission Bay, thus fostering conversation, insight, and collaboration across fields.
In addition, UCSF itself is a graduate-level-only institution with a singular focus on health. Within the campus, the School of Pharmacy, in which the Department of Pharmaceutical Chemistry and the Renslo Lab sit, focuses on improving health through therapeutics. Thus from lab to department to school to campus, UCSF is a rich and supportive environment for health science research, including innovative research dedicated to improving the world’s arsenal of therapeutics to prevent and treat disease.
The Renslo Lab comprises staff scientists, postdoctoral researchers, and graduate students. This combination suits the translational nature of our research and provides a stimulating environment for postdoctoral scholars and PhD students. Our staff scientists possess many years of medicinal chemistry experience, much of it gained in the pharmaceutical industry. The lab is fortunate to have recruited postdoctoral researchers from top-notch synthetic chemistry labs and talented PhD students from the Chemistry and Chemical Biology Graduate Program at UCSF. More: People.