Research Interests
Mission:
The Center for Integrative Chemical Biology and Drug Discovery (CICBDD) was created with the mission of bringing dedicated medicinal chemistry expertise to bear on biological targets of therapeutic relevance under investigation by UNC faculty. Synthetic chemists, assay development and compound profiling scientists will work in the Center and create dedicated, multidisciplinary project teams with other groups on campus in order to progress targets through the drug discovery and development process.

Context:
Scientific progress in the biomedical sciences has accelerated enormously over the last 2-3 decades. The cellular signal transduction processes and biochemical pathways that enable life are increasingly understood at the molecular level and the aberrations that result in disease can be defined within this rational context. Additionally, with the sequencing of the human and other genomes, the identity of the cast in this drama of life is known with ever greater certainty. Technology to enable discovery of ligands for molecular targets has also advanced such that many complimentary approaches exist for creating small molecule tools to interrogate biological processes. However, even as basic science and technology seem poised to create a revolution in the availability of potent, selective and safe small molecule drugs, the pharmaceutical industry, where >90% of drugs have historically been discovered, is struggling for survival. While industry investment in R&D has grown exponentially, the return in terms of New Chemical Entities (NCEs) approved as medicines has stagnated and pricing pressures and litigation have further eroded profitability. These conditions have resulted in frequent mergers, reorganizations and reductions in scientific staff across the industry. This is highly disruptive to drug discovery projects which must survive several generations of R&D management during their >10 year life span. Given the rate of organizational change in the industry, it is increasingly difficult for a research strategy to bear fruit before it is abandoned. Additionally, there is a growing trend for larger pharmaceutical companies to outsource and externalize the early phases of drug discovery via either active partnerships or opportunistic in-licensing of NCEs. In this context, there is a clear societal need for greater organizational diversity and innovation in how drugs are discovered in order for advances in biomedical research to result in new medicines. Exclusive (>90%) reliance on large pharmaceutical companies for drug discovery will not suffice.

UNC possesses the scientific and medical talent to contribute substantially to the discovery of small molecule drugs; however, each new insight into human biology with potential therapeutic relevance faces similar challenges in translation the lack of an experienced and dedicated chemistry/biology team to drive projects from target identification through lead or candidate discovery. The creation of the CICBDD will fill a key gap in expertise and resources at UNC and enable translation of basic scientific discoveries into potential human therapeutics. Importantly, the research culture of the University is based upon fostering innovation and nurturing new ideas qualities that are essential for improving the success of early discovery efforts.

In addition to the expertise in basic biological sciences present in Pharmacology, Biochemistry, the Cancer Center and the Medical School, the School of Pharmacy has several initiatives that will strongly synergize with the drug discovery focus of the CICBDD: The Center for Nanotechnology in Drug Delivery (CNDD), the Institute for Pharmacogenomics and Individualized Therapy (IPIT) and the National Institute of Mental Health Psychoactive Drug Screening program (NIMH-PDS). State of the art drug delivery systems developed in the CNDD will permit rapid progression of small molecules into a broad and genetically characterized set of animal models, provided by the IPIT & the NIMH-PDS, which will create an enormously powerful mechanism for rapid target validation & compound profiling. UNCs strengths in transgenic and knock-out technologies are globally recognized as reflected in the recent award of the Nobel prize in Medicine and the Center will take advantage of these capabilities. The co-location of these efforts will greatly enhance successful translation of projects through the discovery and early development stages.

Resources & Portfolio:
The Center has been initiated with funding from across the University and a significant contribution from the Cancer Research Fund (recently created by the State legislature). This initial funding and the facilities devoted to the Center will enable:
10 medicinal/synthetic chemists including two research associate/assistant Professor positions
5 assay development & compound profiling scientists one research assistant Professor
1 computational/informatics research assistant Professor
Creation of a UNC compound collection to be held & assayed at the Biomanufacturing Research Institute and Technology Enterprise (BRITE) at NC Central University a key collaborator for high throughput screening
Capability to outsource synthetic chemistry to enhance productivity

Technology and Strategies:
Hit generation
o Assay development & high throughput screening with a diverse, developable compound collection (BRITE-NCCU)
o Knowledge-based focused screening sets built on target-class, structural and computational models
o Target specific mechanism and/or pharmacophore based design
Hit to pre-candidate selection
o Parallel solution-phase synthesis to pursue 2-3 series per target applying multiple objective optimization
o Structure-driven design where feasible
o Compound profiling for efficacy & selectivity (NIMH-PDS)
o Early dmpk and physical property assessments (CNDD)
o Early focus on enabling translational medicine to verify mechanistic hypothesis animal studies enabled with pharmacodynamic read-out of effect on target (IPIT)
Provision of small molecule reagents
o Assist in the discovery of PET ligands, FP-ligands and small molecule probes of biological targets and pathways

Portfolio Creation & Scientific Advisory Board:
The CICBDD resource will support progression of 3-5 targets at steady-state with a projected turnover of 2-3 targets per year. Proposals for targets will be reviewed by the scientific advisory board for the Center:

Alex Tropsha, Medicinal Chemistry
Bryan Roth, Screening Program Director
Gary Johnson, Pharmacology
Matt Redinbo, Chemistry & Biochem
David Lawrence, Chemistry & Medchem
Ned Sharpless, Cancer center
Russ Mumper, Nanotechnology & Drug Delivery
Howard Mcleod, Pharmacogenomics
Scott Forrest, Tech transfer office

Criteria for evaluation include:
Disease relevance of target/pathway
Potential scientific impact of small molecule tools
Tractability of assay development and ligand discovery
Portfolio balance and fit with center expertise

Timelines:
Initial proposals to the center from faculty will be reviewed with target and project selections made by the end of 2007. Outsourcing of synthetic chemistry can commence in January coincident with the anticipated starting date of the first recruits to the Center. Laboratories for the Center will be in the Genetics Medicine building and will be occupied upon its completion (April 08). The Center will be fully staffed by mid-2008. It is anticipated that the CICBDD will occupy space in the new BRIC building to be completed by 2012/13 and any growth in resources could take place at that time if warranted based upon success.

Measures of success:
Generation of UNC composition of matter intellectual property on 2-3 chemical series per year with potential utility in treating disease beginning in 2008
Enable interrogation of biology with small molecules resulting in enhanced funding of new UNC grant proposals beginning in 2008
Deliver 1 or more pre-clinical candidates per year beginning in 2010
Out license one project and/or create one spin-out company per year beginning in 2010
Establish external collaborations and funding base such that the Center can grow significantly beyond 2010
Create strong academic program within the Center that competes effectively for external funding in a defined area of chemical biology by 2010
Partner with other existing Centers (CNDD, IPIT, NIMH-PDS) to accelerate clinical development of NCEs
Create mechanisms for student and faculty training and enrichment in the areas of expertise within the Center by 2010

Conclusions:
The University is poised to complete the cycle from basic scientific research through translational drug discovery to clinical studies in patients. The scientific opportunities, the unmet needs in healthcare and the need to diversify approaches to drug discovery are compelling. With the creation of the Center for Integrative Chemical Biology and Drug Discovery and the other initiatives mentioned above, UNC is making a bold move which will establish it as a premiere institution for integrated healthcare, enhance the economic development of the State, and further develop the Universitys capabilities to educate and train the scientists and leaders of the future.

Recent Accomplishments and Honors
1993 CEOs Award, Glaxo Research Institute (Special award for leadership of the 5reductase project that led to Avodart GSK marketed product)
American Chemical Society, Organic Division Fellowship 1986-87
1986 University of North Carolina, Off Campus Graduate Fellowship
1985-86 University of North Carolina, Board of Governors Fellowship in Science and Technology
1984 University of North Carolina, Department of Chemistry, Dobbins Fellowship
1983 University of North Carolina, Department of Chemistry, Reilley Fellowship
1983 Graduated summa cum laude from NCSU

Training
North Carolina State University BS 1983 Chemistry
University of North Carolina Chapel Hill PhD 1987 Organic Chemistry

Publications
Discovery and Development of Dutasteride, a Potent Dual 5-Reductase Inhibitor, Stephen V. Frye. Current Topics in Medicinal Chemistry 2006, 6, 405-421.
A prodrug approach to the design of cRaf1 kinase inhibitors with improved cellular activity. Wood, Edgar; Crosby, Renae M.; Dickerson, Scott; Frye, Stephen V.; Griffin, Robert; Hunter, Robert; Jung, David K.; McDonald, O. Bradley; McNutt, Robert; Mahony, William B.; Peel, Michael R.; Ray, John; Lackey, Karen. Anti-Cancer Drug Design 2001, 16(1), 1-6.
Oxindole-Based Inhibitors of Cyclin-Dependent Kinase 2 (CDK2): Design, Synthesis, Enzymatic Activities, and X-ray Crystallographic Analysis. Bramson, H. Neal; Corona, John; Davis, Stephen T.; Dickerson, Scott H.; Edelstein, Mark; Frye, Stephen V.; Gampe, Robert T., Jr.; Harris, Phil A.; Hassell, Anne; Holmes, William D.; Hunter, Robert N.; Lackey, Karen E.; Lovejoy, Brett; Luzzio, Michael J.; Montana, Val; Rocque, Warren J.; Rusnak, David; Shewchuk, Lisa; Veal, James M.; Walker, Duncan H.; Kuyper, Lee F. Journal of Medicinal Chemistry 2001, 44(25), 4339-4358.
The discovery of potent cRaf1 kinase inhibitors. Karen E. Lackey*; Michael Cory; Ronda Davis; Stephen V. Frye; Philip A. Harris; Robert N. Hunter; David K. Jung; O. Bradley McDonald; Robert W. McNutt; Michael R. Peel; Randy D. Rutkowske; James M. Veal; Edgar R. Wood Bioorg. Med. Chem. Lett. 2000, 10(3), 223-226.
"Structure-Activity Relationship Homology (SARAH): A Conceptual Framework for Drug Discovery in the Genomic Era", Stephen V. Frye, Chemistry & Biology, 1999, 6, R3-R7.
TNFconverting enzyme. Marcia Moss*; J. David Becherer*; Marcos Milla; Gregory Pahel; Mill Lambert; Rob Andrews; Stephen Frye; Curt Haffner; David Cowan; Patrick Maloney; Eric P. Dixon; Marilyn Jansen; Michael P. Vitek; Justin Mitchell; Tony Leesnitzer; Janet Warner; James Conway; D. Mark Bickett; Mike Bird; Richard Priest; John Reinhard; Peiyuan Lin In Metalloproteinases Targets Anti-Inflammatory Drugs; Kevin M. K. Bottomley, David Bradshaw; John S. Nixon, Eds.; Birkhaeuser Verlag, Basel, Switz 1999, 187-203.
Discovery and Development of GG745, a Potent Inhibitor of Both Isozymes of 5-Reductase, Stephen V. Frye*, H. Neal Bramson, David J. Hermann, Frank W. Lee, Achintya K. Sinhababu, and Gaochao Tian In Integration of Pharmaceutical Discovery and Development: Case Histories; R.T. Borchardt, R.M. Freidinger, T. Sawyer and P. Smith, Eds.; Plenum Press;1998, 11, 393-422.
Inhibition of Human Steroid 5-Reductases type I and II by 6-Aza-Steroids: Structural Determinants of One-Step vs Two-Step Mechanism, Marcia L. Moss*, Petr Kuzmic, J. Darren Stuart, Gaochao Tian, Anne G. Peranteau, Stephen V. Frye, Sue H. Kadwell, Thomas A. Kost, Laurie K. Overton and Indravadan R. Patel, Biochemistry, 1996, 35, 3457-3464.
Inhibitors of 5-Reductase, Stephen V. Frye, Current Pharmaceutical Design, 1996, 2, 59-84.
Mechanism of Time -Dependent Inhibition of 5-Reductases by 1-4-Azasteroids: Toward Perfection of Rates of Time-Dependent Inhibition by Using Ligand Binding Energies, Gaochao Tian*, Robert A. Mook, Jr., Marcia L. Moss, and Stephen V. Frye, Biochemistry, 1995, 34, 13453-13459.
Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5 -Reductase and Human Adrenal 3-Hydroxy-5-steroid Dehydrogenase/3-Keto-5-steroid Isomerase by 6-Azaandrost-4-en-3-ones: Optimization of the C17 Substituent, Stephen V. Frye,* Curt D. Haffner, Patrick R. Maloney, Roger N. Hiner, George F. Dorsey,Jr., Robert A. Noe, Rayomand J. Unwalla, Kenneth W. Batchelor, H. Neal Bramson, J. Darren Stuart, Stephanie L. Schweiker, John van Arnold, D. Mark Bickett, Marcia L. Moss, Gaochoa Tian, Frank W. Lee, Timothy K. Tippin, Michael K. James, Mary K. Grizzle, James E. Long, and Dallas K. Croom, J. Med.Chem. 1995, 38, 2621-2627.
6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5-Reductase and Human Adrenal 3-Hydroxy-5-steroid Dehydrogenase/3-Keto-5-steroid Isomerase, Stephen V. Frye,* Curt D. Haffner, Patrick R. Maloney, Robert A. Mook, Jr., George F. Dorsey,Jr., Roger N. Hiner, Cindy M. Cribbs, Thomas N. Wheeler, John A. Ray, Robert C. Andrews, Kenneth W. Batchelor, H. Neal Bramson, J. Darren Stuart, Stephanie L. Schweiker, John van Arnold, Sharon Croom, D. Mark Bickett, Marcia L. Moss, Gaochoa Tian, Rayomand J. Unwalla, Frank W. Lee, Timothy K. Tippin, Michael K. James, Mary K. Grizzle, James E. Long, and Suzanne V. Schuster, J. Med.Chem. 1994, 37, 2352-2360.
6-Azasteroids: Potent Dual Inhibitors of Human Type 1 and 2 Steroid 5Reductase, Stephen V. Frye*, Curt D. Haffner, Patrick R. Maloney, Robert A. Mook, Jr., George F. Dorsey, Jr., Roger N. Hiner, Kenneth W. Batchelor, H. Neal Bramson, J. Darren Stuart, Stephanie L. Schweiker, John van Arnold, D. Mark Bickett, Marcia L. Moss, Gaochoa Tian, Rayomand J. Unwalla, Frank W. Lee, Timothy K. Tippin, Michael K. James, Mary K. Grizzle, James E. Long and Suzanne V. Schuster, J. Med. Chem. 1993, 36, 4313-4315.
Synthesis of 2-Aminobenzophenones via Rapid Halogen-Lithium Exchange in the Presence of a 2-Amino-N-methoxy-N-methylbenzamide, Stephen V. Frye*, Marty C. Johnson and Nicole L. Valvano, J. Org. Chem. 1991, 56, 3750-3752.
Chelates as Intermediates in Nucleophilic Additions to Alkoxy Ketones According to Crams Rule (Cyclic Model), Xiangning Chen, Edwin R. Hortelano, Ernest L. Eliel* and Stephen V. Frye*, J. Am. Chem. Soc. 1992,114, 1778-1784.
Asymmetric Synthesis and Crams (Chelate) Rule, Ernest L. Eliel*, Stephen V. Frye, Edwin R. Hortelano, Xianging Chen and Xu Bai, Pure & Appl. Chem. 1991, 63, 1591-1598.
Are Chelates Truly Intermediates in Crams Chelate Rule?, Xiangning Chen, Edwin R. Hortelano, Ernest L. Eliel* and Stephen V. Frye*, J. Am. Chem. Soc. 1990,112, 6130-6131.
Asymmetric Synthesis Based On 1,3-Oxathianes-4. Mechanism of Asymmetric Induction in the Reactions of Oxathianyl Ketones, Stephen V. Frye and Ernest L. Eliel*, J. Am. Chem. Soc. 1988,110, 484-489.
Chiral 1,3-Oxathiane From (+)-Pulegone [Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin], Ernest L. Eliel*, Joeph Lynch, Fumitake Kume and Stephen V. Frye, Org. Syntheses 1987, 65, 215-223.
Rapid Injection Nuclear Magnetic Resonance Investigation of the Reactivity of - and -Alkoxyketones with Dimethylmagnesium. Kinetic Evidence for Chelation, Stephen V. Frye*, Ernest L. Eliel and Roland Cloux, J. Am. Chem. Soc. 1987,109, 1862-1863.
Prevention of Chelation by an Oxygen Function Through Protection with a Triisopropylsilyl Group, Stephen V. Frye and Ernest L. Eliel*, Tetrahedron Lett. 1986, 27, 3223-3226.
Nonenzymatic Asymmetric Synthesis of (R)-(-)- and (S)-(+)-Mevalolactone in High Enantiomeric Purity, Stephen V. Frye and Ernest L. Eliel*, J. Org. Chem. 1985, 50, 3402-3404.
Asymmetric Synthesis of (R)- and (S)-Citramalate in High Enantiomeric Purity, Stephen V. Frye and Ernest L. Eliel*, Tetrahedron Lett. 1985, 26, 3907-3910.

E-mail: SVFRYE@EMAIL.UNC.EDU
Telephone: 919-843-5486
Address: Beard Hall Chapel Hill, NC 27599

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