Guthikonda Lecture Series: Dr. Stuart L. Schreiber
About the Seminar:
"Towards a Patient-Based Drug Discovery"
Small-molecule drugs were originally discovered using compound-based drug discovery: opportunistic discovery of a biologically active compound, often a natural product (e.g. penicillin) followed by a seaerch for a disease that might be treated with the compound. This remains a common approach to modern drug discovery (e.g. rapamycin and analogs for use as antifungal agents; immune suppresion agents; anti-cancer agents; possibly others in the future).
The advent of recombinant DNA accelerated a second approach - target-based drug discovery - where the therapeutic target is selected and subjected to methods that yield candidate drugs (mechanism-based design; structure-based design; screening). But this approach has its shortcomings - 97% of drug candidates that enter into clinical investigation eventually fail, many due to unanticipated toxicity and many others due to a lack of efficacy despite successful modulation of the target. Selecting therapeutic targets based on information derived from surrogates of patients has proved challenging.
Advances in human biology, including human genetics and physiology, and in small-molecule science, including chemistry and chemical biology, are now accelerating a third approach - patient based drug discovery. This lecture will present examples that aim to use: 1) information from heritable or somatic human genetics in human disease; for example, in Crohn's Disease and cancer, 2) advances in diversity-oriented synthetic chemistry and chemical biology to accelerate the discovery of safe and effective small-molecule therapeutics, and 3) an understanding of the relationship of human genetic variation to drug efficacy.
About the Speaker:
Stuart L Schreiber, PhD is Director of Chemical Biology and Founding Member of the Broad Institute of Harvard and MIT, where he is a Howard Hughes Medical Institute Investigator. He is also the Morris Loeb Professor of Chemistry and Chemical Biology at Harvard University.
Dr Schreiber develops systematic ways to explore biology, especially disease biology, using small molecules and for his role in the development of the field of chemical biology. He has discovered principles that underlie information transfer and storage in cells, specifically discoveries relating to signaling by the phosphatase calcineurin and kinase mTOR (demonstrating for the first time that drugs can result from the targeting of protein kinases and protein phosphatases), gene regulation by chromatin-modifying histone deacetylases, small-molecule dimerizers that activate cellular processes by enforced proximity, and small-molecule probes of extremely difficult targets and processes (e.g. transcription factors, oncogenes, protein/protein interactions, transdifferentiation) that directly relate to human disease. His work has contributed to diversity-oriented synthesis (DOS) and discovery-based small-molecule screening in an open data-sharing environment, and it resulted in the development of the first public small-molecule screening database named ChemBank. His research has been reported in over 500 publications (H index = 123).
Four new anti-cancer drugs that target proteins discovered in the Schreiber laboratory using his small-molecule approach have been approved by the US FDA: torisel (Wyeth) and afinitor (Novartis; both for renal cancer), which target mTOR (discovered using rapamycin in 1994) and vorinostat (Merck; for cutaneous T-cell lymphoma), which targets HDACs (HDAC1 discovered using trapoxin in 1996). Human clinical trials are underway using a small-molecule dimerizer-based drug (AP1903) to regulate vaccine therapy for the treatment of advanced prostate cancer. In addition, proteins first shown by Schreiber to be targeted by a small molecule have been validated therapeutically by the FDA-approval process: tacrolimus (immunosuppression/1994; Schreiber’s study of FK506) and bortezomib (multiple myeloma/2003; Schreiber’s study of lactacystin), and the pharmaceutical industry has now invested over $100MM in DOS as a new means to discover drugs. Schreiber also extended chemical biology principles to medicine by participating in the founding of three public biopharmaceutical companies with a combined market cap of over $8B: Vertex Pharmaceuticals (1989), ARIAD Pharmaceuticals (1991) and Infinity Pharmaceuticals (2001), each of which has devised new therapeutic agents that are being tested in human clinical trials or used as FDA-approved drugs.