Our lab uses small molecules and engineered proteins to address some of the most challenging problems in chemical biology and early-stage drug discovery.
Research led by Michelle Arkin, PhD, focuses on developing new molecules that interact with proteins. By modulating biological processes, these new molecules, known as chemical probes, teach us how cells function and how proteins are involved in disease. These molecules serve as starting points for drug discovery.
Small molecules and engineered proteins help us fight disease
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. The use of such compounds to understand biology is called chemical biology. The Arkin Lab also works to understand the proteins that underlie diseases. By altering protein structures, they can better understand protein function and can engineer new functions that mimic or modify the disease.
Lab researchers use several methods to discover molecules, including high-throughput screening and fragment-based discovery. High-throughput screening takes many forms, from measuring binding of two proteins, to enzymatic activity, to high-content imaging. 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 Lab, the Renslo Lab, and the Wells Lab at UC San Francisco.
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:
Issue #1: finding solutions for undruggable proteins
Many proteins 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 them. 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. Furthermore, these protein complexes tend to exist within protein-protein interaction networks. Lab research is aimed at understanding how the network is altered in disease and how altering one protein complex might impact the larger network.
Issue #2: developing quantitative assays for complex biology
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, model organisms, and human cells. Our goal is to gain quantitative insights into biological systems that have previously been amenable to only descriptive assays.
Biomedical research is at a critical juncture. The explosion of knowledge about disease processes has led to many new potential drug targets to treat major unmet medical needs; however, many of these potential new targets are considered difficult to modulate with small molecule drugs. Our lab is dedicated to adapting state-of-the-art drug-discovery technologies to address novel target classes and to develop a deep understanding of how drugs affect protein functions. When such compounds demonstrate their value in modulating disease processes, they can seed the effort to develop new medicines.
Drug discovery is a complex science involving biology, chemistry, pharmacology, and engineering. At UCSF, the merger of novel biology, innovative chemical biology, and a focus on biomedical research, puts the Arkin Lab and UCSF in an excellent position to impact human health. 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 in the Department of Pharmaceutical Chemistry of the UCSF School of Pharmacy and located on the Mission Bay campus. Mission Bay is a thriving research ecosystem. It is home to several institutes for biomedical research, including the Cardiovascular Research Institute (CVRI), the Institute for Neurodegenerative Disease (IND), the Helen Diller Family Comprehensive 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 support the formation of new science-based companies, and to encourage academic/industrial partnerships, and the Quantitative Biosciences Institute (QBI), which facilitates interdisciplinary and applied research. Arkin is an investigator in the Chemical Biology Consortium (part of the National Cancer Institutes’ Experimental Therapeutics Program) and the Tau Consortium. The lab also collaborates with pharmaceutical companies (Novartis, Genentech, Janssen, Pfizer, ShangPharma) 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, healthcare professionals, and new pharmaceutical scientists. She is the reviews editor for Cell Chemical Biology, an editor and author of the Assay Guidance Manual and editor of a web series in drug discovery for Henry Stewart Talks. Arkin is a founding member and current president of the board of directors of the Academic Drug Discovery Consortium, whose goals are to build a worldwide scientific network; facilitate collaborations with academic, contract, and pharmaceutical labs; and support drug-discovery education.
She 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 led the biology group for teams that developed potent inhibitors of protein-protein interactions, including interleukin-2/receptor and LFA-1/ICAM. One of these molecules, lifitegrast, is an approved drug for autoimmune dry eye (licensed to SARcode and developed by 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 biochemistry, structural biology, cell biology, and high-throughput screening (HTS). The biochemistry group includes postdoctoral scholars, graduate students, and specialists focused on compound discovery and characterization projects. The HTS team includes three staff scientists who specialize in developing and automating enzymatic-, binding-, and cell-based assay formats. The team also includes an informatics specialist who manages data for HTS and compound-optimization projects, writes software, and mines data. More: Small Molecule Discovery Center, People.