Stephen V. Frye
Stephen V. Frye
CURRICULUM VITAE
PERSONAL
UNC Eshelman School of Pharmacy
The University of North Carolina at
Chapel Hill
Genetic Medicine Building
Campus Box 7363
Chapel Hill, NC 27599-7363
Office: 919 843-5486
Mobile: 919 260 3118
svfrye@email.unc.edu
http://www.pharmacy.unc.edu/labs/cent
er-for-integrative-chemical-biology-anddrug-discovery
Born March 8, 1961 in Greensboro,
North Carolina
Married for 29 years to Susan B. Frye
and have three children (Aaron 22,
Jeremy 21, Rachel 16).
EDUCATION
American University, Washington DC, Oct. 1997- Dec. 1998
Graduate certificate in Organizational Change-Leadership
University of North Carolina at Chapel Hill, 1983 -1987
Major: Organic Chemistry Advisor: Prof. Ernest L. Eliel
Ph.D. May 1987
Dissertation: Stereoselective Syntheses Based on Chiral 1,3-Oxathianes:
Synthesis of Mevalolactone and Citramalic Acid and Investigation of the
Mechanism of Diastereoselection
Off Campus Graduate Fellow, Institut de Chemie Organique, de Université
de Lausanne, Switzerland, March-September 1986
North Carolina State University, 1979-1983
Major: Chemistry Minor: Polymer/Textile Chemistry
B.S. Summa Cum Laude with Honors, May 1983
PROFESSIONAL EXPERIENCE
University of North Carolina at Chapel Hill
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Stephen V. Frye
Fred Eshelman Distinquished Professor, Division of Medicinal Chemistry,
and Director, Center for Integrative Chemical Biology and Drug Discovery
School of Pharmacy (June 2012 - present)
Professor, Division of Medicinal Chemistry, and
Director, Center for Integrative Chemical Biology and Drug Discovery
School of Pharmacy (Nov. 2011 – May 2012)
Research Professor, Division of Medicinal Chemistry, and
Director, Center for Integrative Chemical Biology and Drug Discovery
School of Pharmacy (2007- Nov. 2011)
Member, Molecular Therapeutics, Lineberger Comprehensive Cancer
Center
Adjunct Professor, Department of Chemistry
Key Responsibilities – Responsible for vision, creation and
productivity of a new research center at UNC focussed on chemical
biology and drug discovery.
Glaxo, Glaxo-Wellcome and GlaxoSmithKline (1987-2007)
Key Drug Discovery Accomplishments while employed at GSK:


Project leader and co-inventor of GSK’s 5-reductase inhibitor (Avodart,
dutasteride; FDA approved for treatment of benign prostatic hyperplasia; >
$1 billion world-wide sales in 2010).
Created a global kinase chemistry team that discovered Tykerb (dual
erbB2 and EGFR inhibitor, approved for the treatment of metastatic breast
cancer) and Pazopanib (VEGF inhibitor approved for the treatment of
renal carcinoma).
Scientific, Management and Leadership Roles:
World Wide Vice President, High Throughput Chemistry & Discovery
Medicinal Chemistry, Molecular Discovery Research, GSK (July 2000August 2007)
Key Responsibilities – lead staff of up to 200 internal chemists and
>100 external chemists accountable for all hit to lead and prospective
compound collection building chemistry globally in GSK.
Budget responsibility for $50M operational and $3-5M capital per annum.
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Stephen V. Frye
Research Unit Head, Chemistry Division, Glaxo Wellcome R&D,
Stevenage, UK (overseas assignment, July 1999-July 2000)
Department Head, Medicinal Chemistry, Glaxo Wellcome Inc., RTP
(January 1998 – July 1999)
Principal Research Scientist, Glaxo Wellcome Inc., RTP (February 1997
– December 1997)
Department Head, Medicinal Chemistry, Glaxo Wellcome Inc., RTP (July
1995 - February 1997)
Senior Research Investigator II, Chairman of the Cancer Scientific
Forum, Glaxo Research Institute, Department of Medicinal Chemistry,
RTP (September 1994 - July 1995)
Senior Research Investigator and Project Leader, Glaxo Research
Institute, Department of Medicinal Chemistry, RTP (January 1991September 1994)
Senior Scientist, Glaxo Research Institute, Department of Medicinal
Chemistry, RTP (August 1987-January 1991)
Adjunct Assistant Professor, University of North Carolina at Chapel Hill,
Department of Chemistry (January 1990-January 1995)
Honors, Fellowships & Awards
CEO’s Award 1993, Glaxo Research Institute (Special award for
leadership of the 5-reductase project that led to Avodart)
American Chemical Society, Organic Division Fellowship 1986-87
University of North Carolina, Off Campus Graduate Fellowship 1986
University of North Carolina, Board of Governor’s Fellowship in Science
and Technology 1985-86
University of North Carolina, Department of Chemistry, Dobbins
Fellowship 1984
University of North Carolina, Department of Chemistry, Reilley Fellowship
1983
Consulting Activities (2007-2011)
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Stephen V. Frye
Astex Inc.
Intellikine Inc.
Kainos Medicine Inc.
Integrated Oncology Solutions Inc.
Proteostasis Therapeutics Inc.
Sirga Advanced Biopharma Inc.
Syndexa Inc.
Novartis Option Fund
New Leaf Ventures Inc.
Sanofi-Aventis
Eli Lilly
BIBLIOGRAPHY
Publications (*corresponding author)
Recent solicited contributions:
1) “Too many roads not taken”, *Edwards, A.; Isserlin, R.; Bader, G.; Frye, S.;
Willson, T.; Yu, F., Commentary Nature 2011, 470 (7333), p. 163-165.
2) “The art of the chemical probe”, *Frye, S., Commentary, Nature Chem. Bio., 2010
6(3): p. 159-161, (Cited by Faculty of 1000).
3) “Epigenetics: tools and technologies”, *Janzen, W., Wigle, T., Jin, J. & Frye, S.,
Drug Discovery Today: Technologies 2010 7, e59-e65.
4) “Inhibitors paradoxically prime kinases”, *Frye, S.; Johnson, G., News and Views,
Nature Chem. Bio., 2009 5(7): p. 448-449.
5) “Why Academic Drug Discovery?” *Frye, S.; Janzen, B., Editorial for Future
Pharma, August 2009.
Peer reviewed publications/reviews:
Based on research in current role at UNC
6) “Dynamic Reprogramming of the Kinome In Response to Targeted MEK
Inhibition In Triple Negative Breast Cancer”, Duncan, J. S.; Whittle, M. C.;
Nakamura, K.; Abell, A. N.; Midland, A. A.; Zawistowski, J. S.; Johnson, N. L.;
Granger, D. A.; Jordan, N. V.; Darr, D. B.; Usary, J.; Kuan, P.-F.; Smalley, D. M.;
Major, B.; He, X.; Hoadley, K.; Sharpless, N. E.; Perou, C. M.; Gomez, S. M.;
Chen, X.; Jin, J.; Frye, S. V.; Earp, H. S.; Graves, L. M.; Johnson, G. L.* Cell
2012, 149, 307-321.
7) “AMP Is an Adenosine A1 Receptor Agonist”, Rittiner, J. E.; Korboukh, I.; HullRyde, E.; Jin, J.; Janzen, W. P.; Frye, S. V.; Zylka, M. J.* J. Bio. Chem. 2012,
287, 5301-5309.
8) “Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric
Acute Lymphoblastic Leukemia”, Liu, J.; Yang, C.; Simpson, C.; DeRyckere, D.;
Van Deusen, A.; Miley, M. J.; Kireev, D.; Norris-Drouin, J.; Sather, S.; Hunter, D.;
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Stephen V. Frye
Korboukh, V. K.; Patel, H. S.; Janzen, W. P.; Machius, M.; Johnson, G. L.; Earp,
H. S.; Graham, D. K.; Frye, S. V.; *Wang, X. ACS Medicinal Chemistry Letters
2012, dx.doi.org/10.1021/ml200239k.
9) “Structure-Activity Relationships of Methyl-Lysine Reader Antagonists”, Herold,
J.; Ingerman James, L.; Korboukh, V.; Gao, C.; Coil, K.; Bua, D.; Norris, J.;
Brown, P.; Jin, J.; Janzen, W.; Gozani, O.; *Frye, S., Medicinal Chemistry
Communications 2012, 3, 45-51.
10) “Discovery of beta-Arrestin-Biased Dopamine D2 Ligands for Probing Signal
Transduction Pathways Essential for Antipsychotic Efficacy”, Allen, J. A.; Yost, J.
M.; Setola, V.; Chen, X.; Sassano, M. F.; Chen, M.; Peterson, S.; Yadav, P. N.;
Huang, X. P.; Feng, B.; Jensen, N. H.; Che, X.; Bai, X.; Frye, S. V.; Wetsel, W.
C.; Caron, M. G.; Javitch, J. A.; *Roth, B. L.; *Jin, J. Proc Natl Acad Sci U S A
2011, 108, 18488.
11) “Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines”,
Liu, F.; Barsyte-Lovejoy, D.; Allali-Hassani, A.; He, Y.; Herold, J. M.; Chen, X.;
Yates, C. M.; Frye, S. V.; Brown, P. J.; Huang, J.; Vedadi, M.; *Arrowsmith, C. H.;
*Jin, J. J. Med. Chem. 2011, 54, 6139-50. PMID: 21780790.
12) “US Academic Drug Discovery”, *Frye, S.; Crosby, M.; Edwards, T.; *Juliano, R.,
Nature Rev. Drug Disc. 2011, 10, 409-10.
13) “A Chemical Probe Selectively Inhibits G9a and GLP Methyltransferase Activity
in Cells”, Vedadi, M.; Barsyte-Lovejoy, D.; Liu, F.; Allali-Hassan, A.; RivalGervier, S.; Wigle, T.; DiMaggio, P.; Wasney, G.; Siarheyeva, A.; Dong, A.;
Tempel, W.; Chen, X.; Chau, I.; Mangano, T.; Evans, J.; Simpson, C. D.;
Pattenden, S.; Norris, J.; Kireev, D.; Tripathy, A.; Edwards, A.; Roth, B.; Janzen,
W.; Garcia, B.; Ellis, J.; Brown, P.; Frye, S.; *Arrowsmith, C.; *Jin, J., Nature
Chem. Bio. 2011, 7, 566-74.
14) “Drug Discovery Toward Antagonists of Methyl-lysine Binding Proteins”, Herold,
J.; Ingerman, L.; Gao, C.; *Frye, S., Current Chem. Genomics 2011, 5, (suppl. 1M2) 51-61.
15) “Small Molecule Ligands of Methyl-Lysine Binding Proteins”, Herold, J. M.; Wigle,
T.; Norris, J.; Lam, R.; Korboukh, V.; Gao, C.; Ingerman, L.; Kireev, D.;
Senisterra, G.; Vedadi, M.; Tripathy, A.; Brown, P.; Arrowsmith, C.; Jin, J.;
Janzen, W.; *Frye, S., J. Med. Chem. 2011, 54, 2504–251.
16) "Biophysical probes reveal a ‘compromise’ recognition of histone methylation
states by MBT domains", Gao, C.; Herold, J.; *Kireev, D; Wigle, T.; Norris, J.;
Frye, S., J. Am. Chem. Soc., 2011, 133 (14), 5357-5362.
17) “Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of -KetoglutarateDependent Dioxygenases“, Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim,
S.-H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M.-T.; Liu, L.-x.; Jiang, W.-q.; Liu, J.;
Zhang, J.-y.; Wang, B.; Frye, S.; Zhang, Y.; Xu, Y.-h.; Lei, Q.-y.; Guan, K.-L.;
Zhao, S.-m.; *Xiong, Y., Cancer Cell 2011, 19 (1), 17-30 (cover story).
18) “Identification of Non-Peptide Malignant Brain Tumor (MBT) Repeat Antagonists
by Virtual Screening of Commercially Available Compounds”, Kireev*, D.; Wigle,
T.; Norris-Drouin, J.; Herold, J.; Janzen, W.; Frye, S., J. Med. Chem. 2010, 53,
7625-7631.
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Stephen V. Frye
19) “Targeting Methyl-Lysine”, Frye*, S.; Heightman, T.; Jin, J., Annual Reports in
Med. Chemistry 2010, 45, 329-343.
20) "Accessing Protein Methyltransferase and Demethylase Enzymology Using
Microfluidic Capillary Electrophoresis”, Wigle, T.; Provencher, L.; Norris, J.; Jin,
J.; Brown, P.; Frye, S.; *Janzen, W., Chemistry and Biology 2010, 17, 695-704
(cover story).
21) “Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and
Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines”, Liu,
F.; Chen, X.; Allali-Hassani, A.; Quinn, M.; Wigle, T.; Wasney, G.; Dong, A.;
Senisterra, G.; Chau, I.; Siarheyeva, A.; Norris, J.; Kireev, D.; Jadhav, A.; Herold,
J.; Janzen, W.; Arrowsmith, S.; Frye, S.; Brown, P.; Simeonov, A.; Vedadi, M.;
*Jin, J., J. Med. Chem., 2010, 53, 5844-5857.
22) “Screening for Inhibitors of Low Affinity Epigenetic Peptide-Protein Interactions:
An AlphaScreen™-Based Assay for Antagonists of Methyl-Lysine Binding
Proteins”, Wigle, T.; Herold, J. M.; Kireev, D.; Frye, S.; *Janzen, W., J.
Biomolecular Screening 2010, 15, 62-71 (cover story).
23) “Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective
Inhibitor of Histone Lysine Methyltransferase G9a”, Feng, L.; Chen, X.; AllaliHassani, A.; Quinn, A.; Wasney, G.; Dong, A.; Barsyte, D.; Kozieradzki, I.;
Senisterra, G.; Chau, I.; Siarheyeva, A.; Kireev, D.; Jadhav, A.; Herold, J. M.;
Frye, S.; Arrowsmith, C.; Brown, P.; Simeonov, A.; Vedadi, M.; *Jin, J., J. Med.
Chem., 2009, 52(24): p. 7950-3.
Based on research at GSK
24) “Photochemical Rearrangement of a 6-Azasteroid Oxaziridine to a Novel 17Carbomethoxy-A-homo-B-seco-6-aza-3, 5-androstanedione”, *Frye, S., J.
Mexican Chemical Society (special commemorative issue in honor of Ernest
Eliel) 2009, 53(3): p. 131-133.
25) “Discovery and Development of Dutasteride, a Potent Dual 5-Reductase
Inhibitor”, *Frye, S., Current Topics in Medicinal Chemistry 2006, 6, 405-421.
26) “A prodrug approach to the design of cRaf1 kinase inhibitors with improved
cellular activity”, Wood, E.; Crosby, R.; Dickerson, S.; Frye, S.; Griffin, R.;
Hunter, R.; Jung, D.; McDonald, O. B.; McNutt, R.; Mahony, W.; Peel, M.; Ray,
J.; *Lackey, K., Anti-Cancer Drug Design 2001, 16(1), 1-6.
27) “Oxindole-Based Inhibitors of Cyclin-Dependent Kinase 2 (CDK2): Design,
Synthesis, Enzymatic Activities, and X-ray Crystallographic Analysis”,
Bramson, H. N.; Corona, J.; Davis, S.; Dickerson, S.; Edelstein, M.; Frye, S.;
Gampe, Jr., R.; Harris, P.; Hassell, A.; Holmes, W.; Hunter, R.; Lackey, K.;
Lovejoy, B.; Luzzio, M.; Montana, V.; Rocque, W.; Rusnak, D.; Shewchuk, L.;
Veal, J.; Walker, D.; *Kuyper, L., J. Med. Chem., 2001, 44(25), 4339-4358.
28) “The discovery of potent cRaf1 kinase inhibitors”, *Lackey, K.; Cory, M.; Davis, R.;
Frye, S.; Harris, P.; Hunter, R.; Jung, D.; McDonald, O. B.; McNutt, R.; Peel, M.;
Rutkowske, R.; Veal, J.; Wood, E., Bioorg. Med. Chem. Lett. 2000, 10(3), 223-226.
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Stephen V. Frye
29) "Structure-Activity Relationship Homology (SARAH): A Conceptual Framework
for Drug Discovery in the Genomic Era", *Frye, S., Chemistry & Biology, 1999, 6,
R3-R7.
30) “TNFconverting enzyme”, *Moss, M.; *Becherer, J. D.; Milla, M.; Pahel, G.;
Lambert, M.; Andrews, R.; Frye, S.; Haffner, C.; Cowan, D.; Maloney, P.; Dixon, E.;
Jansen, M.; Vitek, M.; Mitchell, J.; Leesnitzer, T.; Warner, J.; Conway, J.; Bickett, D.
M.; Bird, M.; Priest, R.; Reinhard, J.; Lin, P., In Metalloproteinases Targets AntiInflammatory Drugs; Kevin M. K. Bottomley, David Bradshaw; John S. Nixon, Eds.;
Birkhaeuser Verlag, Basel, Switz 1999, 187-203.
31) “Discovery and Development of GG745, a Potent Inhibitor of Both Isozymes of
-Reductase”, *Frye, S.; Bramson, H. N.; Hermann, D.; Lee, F.; Sinhababu, A.;
Tian, G., 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.
32) “The Unique Preclinical Characteristics of GG745, A Potent Dual Inhibitor of 5Reductase”, *Bramson, H. N.; Hermann, D.; Batchelor, K.; Lee, F.; James, M.;
Frye, S., J. Pharm. Exp. Ther., 1997, 282, 1496-1502.
33) “Inhibition of Human Steroid 5-Reductases type I and II by 6-Aza-Steroids:
Structural Determinants of One-Step vs Two-Step Mechanism”, *Moss, M.;
Kuzmic, P.; Stuart, J. D.; Tian, G.; Peranteau, A.; Frye, S.; Kadwell, S.; Kost, T.;
Overton, L.; Patel, I., Biochemistry, 1996, 35, 3457-3464.
34) “Inhibitors of 5-Reductase”, *Frye, S., Current Pharmaceutical Design, 1996, 2,
59-84.
35) “Mechanism of Time -Dependent Inhibition of 5-Reductases by 1-4Azasteroids: Toward Perfection of Rates of Time-Dependent Inhibition by Using
Ligand Binding Energies”, *Tian, G.; Mook, Jr., R.; Moss, M.; Frye, S.,
Biochemistry, 1995, 34, 13453-13459.
36) “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”, *Frye, S.; Haffner, C.; Maloney, P.; Hiner, R.; Dorsey, Jr., G.; Noe,
R.; Unwalla, R.; Batchelor, K.; Bramson, H. N.; Stuart, J. D.; Schweiker, S.;
Arnold, J.v-..; Bickett, D. M.; Moss, M.; Tian, G.; Lee, F.; Tippin, T.; James, M.;
Grizzle, M.; Long, J.; Croom, D.,J. Med.Chem. 1995, 38, 2621-2627.
37) “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”, *Frye, S.; Haffner, C.; Maloney,
P.; Mook, Jr., R.; Dorsey, Jr., G.; Hiner, R.; Cribbs, C.; Wheeler, T.; Ray, J.;
Andrews, R.; Batchelor, K.; Bramson, H. N.; Stuart, J. D.; Schwiker, S.; Arnold,
J.v-; Croom, S.; Bickett, D. M.; Moss, M.; Tian, G.; Unwalla, R.; Lee, F.; Tippin,
T.; James, M.; Grizzle, M.; Long, J.; Schuster, S., J. Med.Chem. 1994, 37, 23522360.
38) “17-(N-tert-Butylcarbamoyl)-4-aza-5-adrostan-1-en-3-one Is an Active SiteDirected Slow Time-Dependent Inhibitor of Human Steroid 5-Reductase 1”,
*Tian, G.; Stuart, J. D.; Moss, M.; Dominico, P.; Bramson, H. N.; Patel, I.;
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Kadwell, S.; Overton, L.; Kost, T.; Mook, Jr., R.; Frye, S.; Batchelor, K.;
Wiseman, J., Biochemistry, 1994, 33, 2291-2296.
39) “6-Azasteroids: Potent Dual Inhibitors of Human Type 1 and 2 Steroid
5Reductase”, *Frye, S.; Haffner, C.; Maloney, P.; Mook, Jr., R.; Dorsey, Jr., G.;
Hiner, R.; Batchelor, K.; Bramson, H. N.; Stuart, J. D.; Schweiker, S.; Arnold, J.v-;
Bickett, D. M.; Moss, M.; Tian, G.; Unwalla, R.; Lee, F.; Tippin, T.; James, M.;
Grizzle, M.; Long, J.; Schuster, S., J. Med. Chem. 1993, 36, 4313-4315.
40) “Synthesis of 2-Aminobenzophenones via Rapid Halogen-Lithium Exchange in the
Presence of a 2-Amino-N-methoxy-N-methylbenzamide”, *Frye, S.; Johnson, M.;
Valvano, N., J. Org. Chem. 1991, 56, 3750-3752.
Resulting from research as adjunct faculty at UNC
41) “Chelates as Intermediates in Nucleophilic Additions to Alkoxy Ketones
According to Cram’s Rule (Cyclic Model)”, Chen, X.; Hortelano, E.; *Eliel, E.;
*Frye, S., J. Am. Chem. Soc. 1992,114, 1778-1784.
42) “Asymmetric Synthesis and Cram’s (Chelate) Rule”, *Eliel, E.; Frye, S.;
Hortelano, E.; Chen, X.; Bai, X., Pure & Appl. Chem. 1991, 63, 1591-1598.
43) “Are Chelates Truly Intermediates in Cram’s Chelate Rule?”, Chen, X.;
Hortelano, E.; *Eliel, E.; *Frye, S., J. Am. Chem. Soc. 1990,112, 6130-6131.
Resulting from PhD research
44) “Asymmetric Synthesis Based On 1,3-Oxathianes-4. Mechanism of Asymmetric
Induction in the Reactions of Oxathianyl Ketones”, Frye, S.; *Eliel, E., J. Am.
Chem. Soc. 1988,110, 484-489.
45) “Chiral 1,3-Oxathiane From (+)-Pulegone [Hexahydro-4,4,7-trimethyl-4H-1,3benzoxathiin]”, *Eliel, E.; Lynch, J.; Kume, F.; Frye, S., Org. Syntheses 1987, 65,
215-223.
46) “Rapid Injection Nuclear Magnetic Resonance Investigation of the Reactivity of
- and -Alkoxyketones with Dimethylmagnesium. Kinetic Evidence for
Chelation”, *Frye, S.; Eliel, E.; Cloux, R., J. Am. Chem. Soc. 1987,109, 18621863.
47) “Prevention of Chelation by an Oxygen Function Through Protection with a
Triisopropylsilyl Group”, Frye, S.; *Eliel, E., Tetrahedron Lett. 1986, 27, 32233226.
48) “Nonenzymatic Asymmetric Synthesis of (R)-(-)- and (S)-(+)-Mevalolactone in
High Enantiomeric Purity”, Frye, S.; *Eliel, E., J. Org. Chem. 1985, 50, 34023404.
49) “Asymmetric Synthesis of (R)- and (S)-Citramalate in High Enantiomeric Purity”,
Frye, S.; *Eliel, E., Tetrahedron Lett. 1985, 26, 3907-3910.
Issued patents and recent filings
50) “Pyrazolopyrimidine Compounds for the Treatment of Cancer”, Wang, X.; Liu, J.;
Yang, C.; Kireev, D., Frye, S., PCT Int. Appl. 2011, WO 2011/146313.
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Stephen V. Frye
51) “Functionally Selective Ligands of Dopamine D2 Receptors”, Jin, J.; Roth, B.;
Frye, S., US61/360,951, provisionally filed 7/2/2010.
52) “Compounds and Methods for Treating Pain and Other Conditions”, Zylka, M.;
Jin, J.; Frye, S., US61/277,136, provisionally filed 9/21/2009.
53) “Preparation of benzo[f]isoindoles as EP4 receptor ligands”, Giblin, G.; Frye, S.;
Roomans, S., PCT Int. Appl. 2002, 33 pp.
54) “Preparation of 4-azaandrostanones as 5-reductase inhibitors”, Batchelor, K.;
Frye, S., US 5998427.
55) “Preparation of azaandrostenones for the treatment of androgen responsive
diseases”, Batchelor, K.; Frye, S., US 5977126.
56) “Preparation of oxindoles as protein tyrosine kinase and protein serine/threonine
kinase inhibitors”, Davis, S.; Dickerson, S.; Frye, S.; Harris, P.; Hunter III, R.;
Kuyper, L.; Lackey, K.; Luzzio, M.; Veal, J.; Walker, D., WO 98-EP5559 19980903.
57) “Inhibitors of 5-Alpha-Testosterone Reductase”, Andrews, R.; Cribbs, C.; Frye,
S.; Haffner, C.; Maloney, P., US 5543406.
58) “Androstenones”, Batchelor, K.; Frye, S., WO 95/07926. Issued in the US:
5,977,126.
59) “Androstenone Derivative”, Batchelor, K.; Frye, S., WO 95/07927. Issued in the
US: 5,565,467.
60) “17--Acyl-6-Azaandrost-4,6-Diazo-4-ene-3-ones”, Frye, S.; Middlemiss, D.;
Fang, F., US 5457098.
61) “Heterocyclic Inhibitors of 5-Alpha-Testosterone Reductase”, Frye, S.;
Middlemiss, D.; Fang, R., US 5302589.
62) “Substituted 6-Azaandrostenones”, Andrews, R.; Cribbs, C.; Frye, S.; Haffner,
C.; Maloney, P., WO 94/14833.
63) “Inhibitors of 5-Alpha-Testosterone Reductase”, Frye, S.; Cribbs, C.; Haffner, C.;
Maloney, P.; Andrews, R., WO 93/13124.
64) “Cobalt Porphyrins”, Johnson, M.; Frye, S., US 5192757.
65) “Cobalt Porphyrin Pharmaceutical Compositions”, Johnson, M.; Frye, S., US
5149697.
66) “Synthesis of 2-Aminobenzophenones”, Johnson, M.; Frye, S., US 5136085.
67) “Synthesis of 2-Aminobenzophenones”, Johnson, M.; Frye, S., US 5053543.
Selected Presentations & Meetings
1) Keynote Speaker “Chemical Biology of Methyl-Lysine”, SBNet 2012, Swedish
Structural Biology Network, Tällberg, June 15th, 2012.
2) Werblow Lecture “Chemical Biology of Methyl-Lysine”, Weill Cornell Medical
College, May 22nd, 2012.
3) Invited Speaker “Chemical Biology of Methyl-Lysine”, Transcription and Cancer
Meeting, Banbury Center, Cold Spring Harbor, April 24th, 2012.
4) Invited Speaker “Chemical Biology of Methyl-Lysine”, Drug Development and
Pharmacogenomics Academy, Emory University, April 4th, 2012.
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Stephen V. Frye
5) Co-chair “Addressing the Challenges of Drug Discovery – Novel Targets, New
Chemical Space and Emerging Approaches”, Keystone Symposia, Tahoe City,
March 19-23, 2012.
6) Invited Speaker “Chemical Biology of Methyl-Lysine”, John Hopkins Department of
Pharmacology, Baltimore, October 20th, 2011.
7) Invited Speaker “Building Academic Drug Discovery Centers”, Drug Discovery in
Academia, Baltimore, October 18th, 2011.
8) Invited Speaker “The Role of Academic Drug Discovery and Chemical Biology of
Chromatin Regulation”, Frontiers in Chemical Biology and Drug Discovery, Stony
Brook SUNY, October 14th, 2011.
9) Invited Speaker “Chemical Biology of Methyl-Lysine”, Vertex, Cambridge, October
7th, 2011.
10) Invited Speaker “Chemical Biology of Methyl-Lysine”, Eli Lilly, Indianapolis,
September 27th, 2011.
11) Invited Speaker “Academic Drug Discovery: US Perspective and Examples”, NCI
Translational Science Meeting, Washington DC, July 29th, 2011.
12) Invited Speaker “Kinase Chemical Probes – Why?” Structural Genomics Consortium
Annual Retreat, Barbados, May 4th, 2011.
13) Invited Speaker “Promoting Illiteracy in Epigenetics: Antagonists of the Readers and
Writers of the Histone Code”, Department Cellular and Molecular Pharmacology,
UCSF, April 18th, 2011.
14) Invited Speaker “Promoting Illiteracy in Epigenetics: Antagonists of the Readers and
Writers of the Histone Code”, Genetech, San Francisco, April 19th, 2011.
15) Invited Speaker “Promoting Illiteracy in Epigenetics: Antagonists of the Readers and
Writers of the Histone Code”, Division of Chemical Biology, Walter & Eliza Hall
Institute of Medical Research, Melbourne, Australia, March 4th, 2011.
16) Invited Speaker “Promoting Illiteracy in Epigenetics: Antagonists of the Readers and
Writers of the Histone Code”, Structural Biology and Drug Discovery Conference,
Cancun, December 2010.
17) Invited Speaker “Chemical Biology Consortium – Overview of Funded Projects”,
American Association of Cancer Institutes, Chicago, October 2010.
18) Invited Speaker & Session Chair, “Why Academic Drug Discovery Makes Sense”,
SBS Symposium, Research Triangle Park, October 2010.
19) Invited Speaker, “Promoting Illiteracy in Epigenetics: Antagonists of the Readers of
the Epigenetic Code”, Jilin University Chemical Biology and Drug Discovery
Symposium, Changchun China, May, 2010.
20) Keynote Speaker, “Chemical Biology of Epigenetics: Antagonists of the Readers and
Writers of the Histone Code”, Alabama Drug Discovery Alliance Symposium,
Birmingham, May 2010.
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Stephen V. Frye
21) Invited Speaker, “Promoting Illiteracy in Epigenetics: Antagonists of the Readers and
Writers of the Epigenetic Code”, American Chemical Society National Meeting, San
Francisco, March 2010.
22) Invited Speaker, “Promoting Illiteracy in Epigenetics: Antagonists of the Readers and
Writers of the Epigenetic Code”, Epigenetic Mechanisms in Health and Disease,
Toronto, Canada, October 2009.
23) Invited Speaker, “Target Identification and Validation in the Context of Gene
Families, a Chemical Biology Perspective” Medicinal Biochemistry Symposium,
UNC-Greensboro, April 2009.
24) Invited Speaker, “Target Identification and Validation in the Context of Gene
Families, a Chemical Biology Perspective”, Karolinska Structural Genomics
Consortium Symposium, Stockholm, Sweden, March 2009.
25) Invited Speaker, “Drug Discovery and Intellectual Property Strategy in
Academia”, Society for Biomolecular Screening, Valley Forge, PA, October 2008.
26) Invited Speaker, “Translational Medicine: Role of Academic Drug Discovery”,
BioPharm America, Atlanta, GA, September 2008.
27) Invited Speaker, “Mechanistic Understanding in Organic Chemistry and Drug
Discovery”, Reaction Mechanisms Conference, Chapel Hill, NC, June 2008.
28) Chair: 2008 Chapel Hill Drug Conference, Chapel Hill, NC, May 16-17.
29) Invited Speaker: “Target Validation and Drug Discovery in the Context of Gene
Families”, European Symposium on Bio-Organic Chemistry, Gregynog, Wales,
May 2007.
30) Invited Speaker: “Target Identification and Validation in the Context of Gene
Families”, Therapeutic Applications of Computational Chemistry and Biology,
Wellcome Trust Conference Center, Hinxton, UK, March 2007.
31) Invited Speaker: “Target-Class Focused High Throughput Chemistry”,
Combinatorial Chemistry Gordon Research Conference, Oxford, UK, August
2006.
32) “Structure Activity Relationship And Homology (SARAH): A Genomic Approach to
Protein Kinase Drug Discovery”, American Association of Cancer Research, New
Orleans LA, March 2001.
33) Co-chair: 2000 Bioorganic Gordon Research Conference, Proctor Academy,
Andover NH, June 18-23.
34) Invited Speaker: “Kinase Systems Based Research: Target Class Science for
Drug Discovery”, University of California at San Francisco & Berkeley, March,
2000.
35) Invited Speaker: “Discovery and Development of GG745, A Potent Inhibitor of
Both Isozymes of 5-Reductase”, Symposium on Urogenital Disease, American
Chemical Society National Meeting, Boston, MA, August, 1998
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Stephen V. Frye
36) Invited Speaker: “Characterization of a Microsomal Metalloendopeptidase That
Processes Tumor Necrosis Factor”, Gordon Research Conference: Bioorganic
Chemistry, Plymouth State College, NH 1996.
37) “6-Azasteroids: Potent Dual Inhibitors of Human Type 1 and 2 Steroid 5Reductase”, American Chemical Society National Meeting, San Diego, CA,
March, 1994.
38) Invited Speaker: “Are Chelates Truly Intermediates in Cram’s Chelate Rule?”,
Gordon Research Conference: Stereochemistry, Salve Regina College, Newport,
RI, 1992.
39) “One-Pot Halogen-Lithium Exchange, N-Methoxy-N-Methylamide Route to 2Aminobenzophenones”, Poster Sesson, French-American Chemical Society,
Captiva Island, Florida, 1991.
40) “Rapid Injection Nuclear Magnetic Resonance Investigation of the Reactivity of
- and -Alkoxyketones with Dimethylmagnesium. Kinetic Evidence for
Chelation”, American Chemical Society National Meeting, Denver, Colorado,
1987.
41) “Prevention of Chelation by an Oxygen Function Through Protection with a
Triisopropylsilyl Group”, American Chemical Society Southeastern Regional
Meeting, Louisville, Kentucky, 1986.
42) “Asymmetric Synthesis of (R)- and (S)-Mevalolactone and (R)- and (S)Citramalic Acid in High Enantiomeric Purity”, American Chemical Society
National Meeting, Chicago, Illinois, 1985.
RESEARCH SUPPORT
ACTIVE
1R01 GM100919-01(Frye)
5/1/12-1/31/16
1.8 calendar months
NIH
$190,000
Discovery of Chemical Probes for Methyllysine Readers
We propose to discover antagonists of the malignant brain tumor (MBT) repeat a structural domain of ca. 100 amino acids which occurs in 9 human proteins
which recognize mono- and dimethyllysine modifications of histones. There are
no known high-quality chemical probes targeting MBT domains. The overarching
objectives of this program are to develop pharmacological probes of methyllysine binding domains to pioneer both the validation of specific domains and the
assay framework in which issues of selectivity and mechanism of action can be
assessed.
1 R01 NS067688-01 (Zylka)
9/25/09-8/31/14
0.24 calendar months
NIH
TDC to CICBDD $825,000; 9/1/2010-8/31/2011 $165,500
Harnessing Ectonucleotidases to Treat Chronic Pain
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Stephen V. Frye
In this application we propose to discover and develop novel pro-drugs targeting
prostatic acid phosphatase for treating chronic pain.
BOA 29XS126 (Frye)
4/20/09-4/19/14
varies by task order (see below)
NCI/SAIC-Frederick, Inc.
North Carolina Comprehensive Chemical Biology Screening Center
This Basic Ordering Agreement was issued by the NCI to members of the
Chemical Biology Consortium to facilitate the discovery and development of new
reagents to treat cancer. Dr. Frye is the Director of the NC Comprehensive
Chemical Biology Screening Center which includes the University of North
Carolina at Chapel Hill, The Hamner Institutes, and North Carolina Central
University. The amount of support will vary depending on the requirements of
the task orders issued.
BOA 29XS126 (Frye, Lead PI) 7/2/10-1/31/12
1.8 calendar months
NCI/SAIC-Frederick, Inc.
$543,002 (Task Order 09)
Target Validation, Assay Development and Hit Discovery for IDH1-Based
Approaches targeting Glioblastoma. This contract award funds specific tasks and
milestones to (1) purify mutant IDH1 proteins and develop an in vitro enzymatic
assay to detect production of α-KG and 2-HG; (2) optimize high-throughput assay
for discovery of inhibitors of mutant IDH1 2-HG production; and (3) tractable hit
discovery as defined in the Statement of Work.
BOA 29XS126 (Frye, Lead PI) 7/13/10-8/12/13
1.8 calendar months
NCI/SAIC-Frederick, Inc. $1,661,940 TDC 8/13/11-8/12/12 (Task Order 07)
Developing Small Molecule Mer Inhibitor Candidates for Novel Treatment of
Acute Lymphoblastic Leukemia. This contract funds specific tasks and
milestones to develop Mer-selective small molecules as drug candidates to treat
ALL and as tool compounds to uncover the mechanism whereby Mer activation
sustains the survival and perhaps contributes to the maturity and niche
adaptation of lymphoid malignancies and selected carcinomas that overexpress
Mer as defined in the Statement of Work.
BOA 29XS126 (Frye)
1/18/11-1/17/12
1.8 calendar months
NCI/SAIC-Frederick, Inc.
$323,962 (Task Order 08)
To provide 1.5 FTE staff positions (project manager and administrative officer)
dedicated to the support and coordination of activities related to the North
Carolina Comprehensive Chemical Biology Screening Center that are not related
to specific projects in order to meet the operational needs of the NCI’s Chemical
Biology Consortium (CBC) and its project activities. In March 2010 SAIC
expanded the scope to include 15% time and effort of the PI that is dedicated to
supervision of support staff awarded under Task Order 08, direction of the
conduct of CBC-related activities that lie outside the scope of awarded task
orders, and oversight of the group of task orders awarded to the North Carolina
Comprehensive Chemical Biology Screening Center.
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Stephen V. Frye
3 U19 MH082441-04S1 (Roth; Project PI – Jin) 1/19/09-4/30/12 0.24 calendar
months
NIH
TDC to CICBDD $679,000; 5/1/10-4/30/11 $224,297
Functional Selectivity: A Novel Approach for CNS Drug Discovery
The overall objectives of this project are to create novel dopamine D2 ligands
with unprecedented patterns of functional selectivity for elucidating the key signal
transduction pathways essential for antipsychotic efficacy, and to discover novel,
functionally selective antipsychotic drug candidates that are safer and more
effective than existing antipsychotics.
1 R03 DA030553-01 (Janzen)
5/1/10-4/30/12
0.12 calendar months
NIDA
TDC $50,000; 5/1/10-4/30/11 $20,000
High-throughput Screening for the Discovery of Novel Scaffolds that Antagonize
Methylated Histone Recognition
The main goal of this proposal is to develop small molecule probes that inhibit
the binding of the L3BMBTL1 methyl lysine binding protein to histone tails by
running a high throughput screening assay at the MLPCN.
COMPLETED
1 RC1 GM090732-01 (Frye)
9/30/09-8/31/11
3 calendar months
NIH Challenge Grant
TDC $591,758; 9/1/10-8/31/11 $298,383
Discovery of Small Molecule MBT Domain Antagonists
We propose to develop potent antagonists of methyl-lysine recognition by human
and Drosophila MBT domain containing proteins in order to permit exploration of
the biological consequences of blocking this recognition in cell based and in vivo
models with relevance to normal and disease biology. Specifically, we propose
to 1) develop biological assays for human and Drosophila MBT containing
proteins; 2) use focused and diversity based screening, virtual screening, and
structure-based design to identify potential antagonists of methyl-lysine
recognition; and 3) optimize hits via iterative design, synthesis, and biological
assessment.
HRSA-09-163(Frye)
09/01/09-6/30/2010
DHHS HRSA
Equipment Only $163,330
Automated Compound Storage System for the Center for Integrative Chemical
Biology and Drug Discovery at the University of North Carolina at Chapel Hill
The award provides partial funding for the acquisition of an automated compound
storage and retrieval system for storing liquid aliquots of the Center’s collection of
small molecules for use in drug discovery and as tool compounds. Samples will
be stored to facilitate cherry-picking compounds or sets of compounds and
arraying them in user specific formats. No salary support is included.
BOA 29XS126 (Frye, Lead PI)
NCI/SAIC-Frederick, Inc.
06/29/12
9/1/09-12/29/09
0.2 calendar months
$31,881 (Task Order 01)
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Stephen V. Frye
For participation in a network collaborative effort to develop a shared curation filter for a
pooled compound file library consisting of the curated libraries of each CBC member
organization using standard criteria agreed upon by all members.
PROFESSIONAL SERVICE
External reviewer for the Higuchi Biosciences Center at U. Kansas, January 2012.
Advisory Committee to the Canadian Cancer Stem Cell Consortium (CSCC), 2011.
Cooperative Research Center for Cancer Therapeutics, Australia, Third Year
Review Panel Member, March 2011
Collaborative Ependymoma Research Network (CERN), Member, 2010-present
St. Jude Children’s Hospital, Chemical Biology and Therapeutics Review Group,
August, 2010
University of Dundee Division of Biological Chemistry and Drug Discovery,
Quinquennial Review Board member, September, 2009
Moffitt Cancer Center P01 External Advisory Board member, January, 2009
National Academy of Sciences invited participant: “The Chemistry Platform for
Pharmaceuticals: A scoping meeting”, August, 2008
Harvard Medical School Therapeutics Strategy Retreat invited speaker, October
2008
North Carolina Drug Discovery Center of Innovation Steering Group and
Scientific Advisory Board, January 2008 - present
Scientific Advisory Committee member of the Structural Genomics Consortium,
August 2007 – present
External Advisory Board Member to UNC Department of Chemistry, 2003 – 2007
Physical and Mathematical Sciences Advisory Board Member, NCSU, 2003 –
present
Peer reviewer for funding agencies
NIH Molecular Libraries Probe Network, Member of Probe Report Review Board,
2010-2011
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Stephen V. Frye
Wellcome Trust, Peer Reviewer, 2010-present
BBSRC UK Research Council, Peer Reviewer, 2011
Research Corporation for Science Advancement, 2009-2010
UNC Gillings Innovation Lab Proposals, Reviewer, 2010
Cancer Research UK, Program Reviewer, 2010
North Carolina Biotechnology Center, Education Enhancement Grant Reviewer,
2009
Peer reviewer for scholarly journals
ACS Medicinal Chemistry Letters
Biochemistry
Bioorganic and Medicinal Chemistry
Drug Discovery Today
Cell
Chemistry and Biology (editorial board member)
Journal of Medicinal Chemistry
Nature
Nature Chemical Biology
Nature Biotechnology
Medicinal Chemistry Communications
Pharmaceutical Research
Proceedings of the National Academy of Sciences
Tetrahedron Letters
Service to UNC-CH
Member of the Chancellor’s Innovation Circle, Chair: Judith Cole, 2009-present
Member of Biochemistry and Biophysics Faculty Search Committee, Chair: Leslie
Parise, 2007-2010
Member of the University Cancer Research Fund Therapeutics Theme Team,
Chair: Ned Sharpless, 2009-present
Service to the School of Pharmacy
Member of Senior Faculty Search Committee, Chair: Hal Kohn, 2010-11
Chair of Faculty Search Committee for Carolina Partnership CICBDD
Recruitment, 2009
Seminar speakers hosted: Kevan Shokat (UCSF), Aled Edwards (U. Toronto),
Cheryl Arrowsmith (U. Toronto), Ben Cravatt (Scripps)
Member of Search Committee for SOP Human Resources Staff Hire, 2008
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Stephen V. Frye
Organized and chaired the 2008 Chapel Hill Drug Conference
PhD Thesis Committees
Tim O’Leary (Jian Liu, Medicinal Chemistry)
Man Lou (Alex Tropsha, Medicinal Chemistry)
Jon Edwards (Matt Redinbo, Chemistry)
Sherket Peterson (Jian Liu, Medicinal Chemistry)
Brett Wallace (Matt Redinbo, Chemistry)
Marty Whittle (Gary Johnson, Pharmacology)
Morgan Chapman (Scott Singleton, Medicinal Chemistry)
Amber King (Hal Kohn, Medicinal Chemistry)
Pierre Morieux (Hal Kohn, Medicinal Chemistry)
Jui-Hua Hsien (Alex Tropsha, Medicinal Chemistry)
Venita Gresham (Howard McLeod, Pharmacotherapy and Experimental
Therapeutics)
David Grawoig (Weeks, Chemistry)
Wei Sun (Zhang, Medicinal Chemistry)
Nate Oien (Lawrence, Medicinal Chemistry)
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