Drug Discovery Faculty
The department has a diverse group of primary and secondary faculty interested in drug discovery. Collaborations between drug discovery, structural and synthetic/computational chemistry groups are encouraged, and there are many exciting inter:disciplinary studies ongoing. The department offers a unique collaborative environment for prospective graduate students to find disease cures as a part of Drug Discovery program.
The research of the primary and secondary faculty have interests in drug discovery are listed below along with a short description of their work.
Karen Anderson - The research in our laboratory is directed toward understanding molecular mechanism of clinically important antimicrobial, anticancer, and antiviral molecular targets with the ultimate goal of developing more effective therapies. Key enzyme targets for the development of therapeutics include - KDO8P synthase (an important target for new antibacterials) and a bifunctional thymidylate synthase:dihydrofolate reductase (TS:DHFR) enzyme from parasites (a target for new antiparasitic drugs). Also ongoing are studies to understanding the molecular mechanisms of normal and aberrant protein signaling and the effects of selectively guided anticancer drugs such as Iressa and Gleevec. Important molecular targets include EGFR, HER:2, PDGFR, and c-kit receptor tyrosine kinases. Another key area of focus involves investigating the mechanisms of HIV reverse transcriptase as well as drug resistance and toxicity that may ultimately aid in the design of better therapeutic agents for the treatment of AIDS.
Anton Bennett - The focus of our laboratory is on the physiological and pathophysiological role of the protein tyrosine phosphatases (PTPs). It is now established that protein tyrosine kinases can serve as therapeutic targets against cancer and potentially other diseases. PTPs, which function in the same signaling pathways that are regulated by PTKs, represent an emerging area for drug discovery. We are particularly interested in identifying small molecule inhibitors to PTPs that are involved in metabolic and skeletal muscle diseases.
Yung-Chi Cheng - Our laboratory is interested in cancer and viral chemotherapy. This includes the discovery of new drug entities. Three clinically used antiviral drugs were discovered in my laboratory, five others are at different stages of clinical development, and four more are still at the preclinical stage of development. The approaches taken for the discovery of new drugs are target oriented approaches toward unique virus gene products and/or cancer replication.
Joseph Contessa Our laboratory develops phenotypic strategies for performing high throughput screens related to cancer biology. This experimental design provides applications for target identification with genome-wide genetic screens (shRNA/Crispr-Cas9) or identification of small molecule inhibitors through chemical library screening. Using these methodologies we are actively investigating the regulation of N-linked glycosylation, a post-translational protein modification that regulates cell surface receptor function.
Craig Crews - The Crews lab is interested in the intersection of chemistry and biology and how chemical biology approaches can be translated into early drug development.Examples of these efforts include the discovery of a new class of proteasome inhibitors, one of which served as the basis for carfilzomib/Kyprolis™, anFDA-approved drug for relapsed/refractorymultiple myeloma, and the PROTAC protein degradation platform for targeting the scaffolding role of proteins that are not addressed using small molecule inhibitors.
Jonathan Ellman - Our laboratory is focused on the development of new strategies to identify potent and selective small molecule inhibitors of therapeutically relevant enzymes, including specific protein tyrosine phosphatases, proteases, and protein arginine deiminases. In addition, our laboratory develops practical and general synthetic methods useful to drug discovery and production such as new methods for the asymmetric synthesis of amines and for achieving efficient bond formation via C-H activation.
Kathryn Ferguson Our laboratory has a long-standing interest in the mechanisms of inhibition of receptor tyrosine kinases (RTKs) by therapeutic antibodies, most notably those that bind the epidermal growth factor receptor (EGFR) - one of the first targets of antibody based drugs to treat cancer. We combine X-ray crystallography cryoEM, biochemistry, computational analysis and cellular studies to evaluate and compare existing antibody drugs, and to learn about mechanisms of resistance to these therapeutic antibodies. We are also developing new mechanism-based antibody therapeutics, drawing on the rich understanding of EGFR family receptor structure and dynamics.
Seth Herzon Research in my laboratory focuses on the synthesis and study of DNA-reactive natural products with an emphasis on elucidating the mechanistic basis of DNA damage. We collaborate extensively with researchers at YSM to evaluate the preclinical potential of our compounds and optimize their structures. A second area of research focuses on elucidating the basis of gut-microbiome-associated diseases. We currently study the effects of small molecules generated by certain commensal bacteria that have been implicated in colorectal cancer formation. Finally, a large proportion of our efforts are dedicated toward developing new antibiotics to treat drug-resistant Gram-negative infections.
Len Kaczmarek - Our laboratory is interested in studying ion channels as possible molecular targets for the design of new therapies. One area of focus is the Slack potassium ion channel(also termed KCNT1)as a therapeutic targetfor the treatment of childhood epilepsiesthat are associated with very severe intellectual disabilities.Both alone and in collaboration with a biopharmaceutical company, our laboratory is developing a range of compounds that can activateor inhibit Slack channels. The discovery of potent and selective compounds will provide a strong impetus for the evaluation of Slack activators as novel therapeutic agents, A second set of targets being investigated by our group, again in collaboration with a biotech company, are Kv3 family voltage-dependent potassium channels. Abnormalities or deficiencies in these channels lead to several different conditions, including spinocerebellar ataxia, disorders of hearing and epilepsy. In addition, levels of Kv3 channels are elevated in Fragile X syndrome, the most common form of inherited intellectual disability, This condition is associated with sensory hypersensitivity and our work indicates that compounds that modulate these channels may be effective therapeutically.
Elias Lolis - My laboratory is interested in finding inhibitors to cytokines and chemokines important for inflammation and cancer. Some of our targets are also parasitic cytokine mimics that evade the immune response and important to human health. We use an iterative cycle of high throughput screening, X:ray crystallography, rational drug design, and structural:activity relationships. We also use molecular biology to discover peptides that are agonists and antagonists.
Marina Picciotto - The Picciotto laboratory studies ligands for nicotinic acetylcholine receptors (nAChRs) as potential therapeutic targets for psychiatric illness. Work at the molecular, systems and behavioral level in mice is then translated in collaboration with clinical researchers to establish relevance in human subjects. For example, we have identified molecular targets for development of medications for anxiety and depression, appetite disorders, addiction and aggression. We hope to identify and develop more selective compounds for patients who do not respond to existing medications and with the expectation that they will have fewer side effects than non:-selective nicotinic compounds.
William Sessa - Our laboratory is interested in optimizing cell permeable peptides as potential anti-inflammatory agents. In addition, we are developing strategies (small molecules, decoy domain and antibodies) to integrate LDL binding to the newly identified receptor, ALK-1. Finally, we are interested in small molecule regulators of N-glycosylation as a target to block cellwall synthesis in bacteria or induce ER stress in cancer cells.
Joseph Schlessinger - Our laboratory is using genetic, structural and biochemical approaches to identity novel targets in the action of normal and oncogenic RTKs that may function as "Achilles heels" and can be utilized for drug discovery. We are using a structure guided drug discovery approach to identify drugs that will overcome the resistance that develops in cancer patients treated with kinase inhibitors such as Gleevec, Iressa, Sutent and Nexavar. We are also developing new therapeutic antibodies and other biological agents that that block specifically block the action of RTKs that function as ‘drivers’ of cancers and other diseases. Finally, we are developing new engineered super agonist cytokines and growth factors to be used for treatments of metabolic diseases and specific cancers.
David Spiegel - The Spiegel Laboratory is interested in integrating synthetic chemistry, immunology, and cell biology in the design of novel small:molecule immunotherapeutics. In particular, the lab is working toward a class of antibody-recruiting small molecules (ARMs) that are capable of enhancing recognition of diverse pathogens by the human immune system. The ARM technology represents an entirely novel therapeutic modality that has the potential to combine benefits of both antibody:based and traditional small-molecule:based strategies. For example, ARMs exhibit high specificity, minimal off:target cytotoxicity, and favorable pharmacokinetics, and also have the potential to initiate long:lasting anti:pathogen immunity. We have successfully employed this approach in targeting both HIV and prostate cancer, and believe that it can be applied quite generally toward other diseases as well
Ben Turk - We take an interdisciplinary approach combining structural biology, combinatorial library screening, biochemistry, and cell biology to understand fundamentally how protein kinases target specific protein substrates in living cells. Based on this work we are pursuing strategies for identifying novel classes of small molecule kinase inhibitors that function by disrupting interactions with substrates. We are particularly interested in kinases that are critical for cell growth, proliferation and survival that constitute established and exploratory targets for cancer therapy.
Dan Wu -We study the signaling mechanisms activated by chemoattractants and Wnts and how these signaling mechanisms function in physiological and pathophysiological processes including inflammation, tumor immunology, tumorigenesis and metabolic diseases. Small molecules and biologicals are being developed to alter these signaling pathways for target validation and therapeutic development.