Our lab seeks to address some of the most challenging problems in chemical biology and early-stage drug discovery. Our tools are small molecules.
Research led by Michelle Arkin, PhD, focuses on developing new molecules that interact with proteins. By modulating biological processes, these new molecules teach us how cells function and how proteins cause disease. They can also serve as starting points for drug discovery.
There are many pressing health problems today, including cancer, neurodegenerative disease, and infectious disease. Arkin’s research team collaborates with other researchers to find small molecules that interfere with these diseases. Small molecules are chemical compounds that have the sizes and properties of drugs.
Arkin Lab researchers use several methodologies to discover these molecules, including high-throughput screening, high-content imaging, and fragment-based discovery. High-content imaging is a microscopy-based method that allows biologists to visualize and quantify changes to living or fixed cells and small organisms. Fragment-based discovery comprises a suite of biophysical methods that monitor the binding of small molecular “fragments” to proteins. One such fragment-discovery technology, called tethering, was pioneered at Sunesis Pharmaceuticals and is being further developed in the Arkin, Renslo, and Wells labs at UCSF.
After the team finds molecules that modulate their target, they study these molecules to measure how the compounds bind to proteins, alter protein function, and affect biological activities inside cells. Arkin Lab scientists then closely collaborate with computational and medicinal chemists who design new molecules with improved function.
Research projects are centered around two key issues in small-molecule discovery.
- Many proteins that are known to be important for disease but are considered “undruggable” because we do not yet understand how to design drug-like compounds that bind to these proteins. For instance, multi-protein complexes are associated with many disease states, and inhibiting formation of such complexes could reverse the disease process. However, it has been very difficult to develop drug-like inhibitors for protein-protein interactions. Work in the Arkin Lab aims to discover such inhibitors and to develop guidelines for what types of protein complexes are amenable to inhibition by drug-sized molecules.
- In drug discovery, it is often necessary to simplify the biological model, such as a cancer cell line, in order to test large numbers of samples. One peril is oversimplifying the model, inadvertently sacrificing relevance for precision. We aim to develop assays that interrogate native biological systems. Using high-content imaging (high-throughput microscopy), we study parasites, human stem cells, and rodent-derived primary cells. Our goal is to gain quantitative insights into biological systems that have previously been amenable to only descriptive assays.
Drug discovery is a complex science involving biology, chemistry, pharmacology, and engineering. Research at UCSF and other major research institutes often provides the key biological insights that point to new therapeutic targets, but only recently have universities had access to the technologies and expertise to translate those biological discoveries into new therapies. We are adapting these technologies to address novel target classes and to develop a deep understanding of how drugs bind to proteins and affect their functions. We also use the tools of drug discovery to tackle diseases with dramatic implications for the health of developing countries.
The highly collaborative culture of UCSF and its institutes fosters interdisciplinary research in chemical biology and drug discovery. The Arkin Lab is part of the Small Molecule Discovery Center (SMDC). (See Facility.) The SMDC is a resource run by the UCSF School of Pharmacy and located on the Mission Bay campus in the Department of Pharmaceutical Chemistry. Mission Bay is a thriving research ecosystem. It is home to several institutes for biomedical research, including the Cardiovascular Research Institute, the Institute for Neurodegenerative Disease, the Cancer Center, and the Gladstone Institutes, as well as several small and large biotechnology companies.
The SMDC is affiliated with the California Institute for Quantitative Biosciences (QB3), whose mission is to facilitate interdisciplinary and applied research, support the formation of new science-based companies, and to encourage academic/industrial partnerships. The SMDC is deeply engaged with this cross-cultural enterprise. It is a charter member of research consortia, including the Chemical Biology Consortium (part of the National Cancer Institutes’ Experimental Therapeutics Program) and collaborates with pharmaceutical companies (Novartis, Genentech, Janssen, Pfizer) through shared grants and sponsored research. The lab’s research agenda is carried out within a larger supportive campus environment devoted exclusively to health and within a School that concentrates on improving health through therapeutics.
Arkin and her colleagues are developing resources to teach the principles and tools of drug discovery to basic scientists, health care professionals, and new pharmaceutical scientists. She is an editor and author of Assay Guidance Manual and editor of a web series in drug discovery for Henry Stewart Talks. Arkin is a founding member of the board of directors of the Academic Drug Discovery Consortium, whose goal is to build a worldwide scientific network; facilitate collaborations with academic, contract, and pharmaceutical labs; and support drug-discovery education.
Arkin earned her PhD in chemistry at the California Institute of Technology and then held a Damon Runyon postdoctoral fellowship at Genentech. She was among the first scientists at Sunesis Pharmaceuticals, where she co-led project teams that developed potent inhibitors of protein-protein interactions, including interleukin-2/receptor and LFA-1/ICAM. One of these molecules, lifitegrast, is currently in phase three trials for autoimmune disease at Shire. From 2005 to 2007, she was the associate director of cell biology at Sunesis and led the translational science team for vosaroxin, an anti-cancer agent in phase three clinical trials.
Lab members include experts in high-throughput screening (HTS) and biochemistry. The HTS team includes four staff scientists who specialize in developing and automating enzymatic-, binding-, and cell-based assay formats. The team also includes two informatics specialists who manage data for HTS and compound-optimization projects, write software, and mine the database. The biochemistry group includes postdoctoral scholars, graduate students, and specialists focused on compound discovery and characterization projects. These scientists specialize in enzymology, protein chemistry, biophysics, and structural biology. More: People.