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John S. McMurray, Ph.D.

Present Title & Affiliation

Primary Appointment

Associate Professor, Department of Experimental Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX

Research Interests

Protein-protein interaction inhibitors, drug design, peptides, organic chemistry

Protein phosphorylation and dephosphorylation are major mechanisms fortransmitting signals in the cell. Protein kinases and phosphatases, as well asSrc homology 2 (SH2) domains, mediate these reactions. In cancer, many of thesesignal transduction pathways are aberrant, leading to unchecked cell growth anddivision.

My laboratory is engaged in research of the synthesis of peptides, aminoacid analogues, and peptide mimetics for use in the development ofpeptide-based inhibitors of signal transduction proteins. Our current targetsare phosphoamino acid binding domains such as the Src homology 2 (SH2) domainand BRCA C-terminal (BRCT) domains.

We are developing chemistries to allow the transport of phosphopeptide-basedcompounds into cells and tissues.  This involves the design ofbioreversible phosphate esters and stabilized peptides.  Currently, we arefocused on STAT3 and STAT6, which bind to cell surface receptors and dimerizevia SH2-phosphotyrosine interactions leading to transcription of genes that contributeto cancer (STAT3) and asthma (STAT6). Starting with a phospho-hexapeptide lead,we have developed a small-molecule peptidomimetic prodrug targeted to the STAT3 SH2 domain that inhibits its activation in whole cells and inhibits growth of ahuman breast tumor model.  Tumor growth is accompanied by a reduction inangiogenesis.  We have developed a similar STAT6 inhibitor thatsignificantly reduces asthma symptoms in a mouse model.   

Weemploy structural biology as much as possible to aid in the design of ourinhibitors.  Collaborations with the local structural biology community atthe University of Houston, the M. D. Anderson Cancer Center, and RiceUniversity have shed insight on the intermolecular interactions between ourinhibitors and their targets.

Education & Training

Degree-Granting Education

1986 University of Houston, Houston, TX, PHD, Chemistry
1977 Pennsylvania State University, State College, PA, BS, Biochemistry

Honors and Awards

2007 Greater Houston Section Award, American Chemical Society

Professional Memberships

American Association for Cancer Research
Member, 2006-present
American Chemical Society
Member, 1979-present
American Peptide Society
Member, 1998-present
Gulf Coast Consortia John S. Dunn, Sr. Consortium for Magnetic Resonance, Houston, TX
Steering Committee Member, 9/2001-present
Gulf Coast Consortia Keck Center for Interdisciplinary Bioscience Training, Houston, TX
Executive Committee Member, 9/2001-present
MDACC Faculty Senate, Houston, TX
Committee Member, 9/2008-8/2011
The University of Texas Graduate School of Biomedical Sciences, Houston, TX
Member, 9/1995-present

Selected Publications

Peer-Reviewed Original Research Articles

1. Mandal PK, Freiter EM, Bagsby AL, Robertson FM, McMurray JS. Efficient synthesis of apricoxib, CS-706, a selective cyclooxygenase-2 inhibitor, and evaluation of inhibition of prostaglandin E2 production in inflammatory breast cancer cells. Bioorg Med Chem Lett 21(20):6071-3, 10/2011. e-Pub 8/2011. PMID: 21903394.
2. Dhanik A, Mcmurray JS, Kavraki L. Modeling Peptidomimetics in complex with the SH2 domain of Stat3. Conf Proc IEEE Eng Med Biol Soc 3(N/A):3229-32, 8/2011. PMID: 22255027.
3. Mandal PK, Gao F, Lu Z, Ren Z, Ramesh R, Birtwistle JS, Kaluarachchi KK, Chen X, Bast RC, Liao WS, McMurray JS. Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. J Med Chem 54(10):3549-63, 5/2011. e-Pub 4/2011. PMID: 21486047.
4. Kannan S, Fang W, Song G, Mullighan CG, Hammitt R, McMurray J, Zweidler-McKay PA. Notch/HES1-mediated PARP1 activation: a cell-type specific mechanism for tumor suppression. Blood 117(10), 1/2011. PMID: 21224467.
5. Robertson FM, Simeone AM, Lucci A, McMurray JS, Ghosh S, Cristofanilli M. Differential regulation of the aggressive phenotype of inflammatory breast cancer cells by prostanoid receptors EP3 and EP4. Cancer 116(11 Suppl):2806-14, 6/2010. PMCID: PMC2889924.
6. Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. Role for the RH Domain of GRK5 and 6 in {beta}2-Adrenergic Receptor and Rhodopsin Phosphorylation. Mol Pharmacol 77(3), 3/2010. e-Pub 12/2009. PMID: 20038610.
7. Mandal PK, Liao WS, McMurray JS. Synthesis of Phosphatase-Stable, Cell-Permeable Peptidomimetic Prodrugs that Target the SH2 Domain of Stat3. Org Lett 11(15):3394-3397, 8/2009. PMCID: PMC2836187.
8. Mandal PK, Limbrick D, Coleman DR, Dyer GA, Ren Z, Birtwistle JS, Xiong C, Chen X, Briggs JM, McMurray JS. Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription. 3: Evaluation and molecular modeling. J Med Chem 52(8):2429-42, 4/2009. PMCID: PMC2735258.
9. Mandal PK, McMurray JS. Application of Triethylsilane and Palladium-Charcoal-Induced Reductions in the Synthesis of Fmoc-Glutamic Acid Analogues. Adv Exp Med Biol 611(3):181-2, 2009. PMID: 19400150.
10. McMurray JS, Mandal PK, Liao WS, Ren Z, Chen X. Inhibition of Stat3 by Cell-Permeable Peptidomimetic Prodrugs Targeted to its SH2 Domain. Adv Exp Med Biol 611(11):545-6, 2009. PMID: 19400306.
11. McMurray JS, Ren Z, Mandal PK, Chen X. Model of Intermolecular Interactions between High Affinity Phosphopeptides and Stat3. Adv Exp Med Biol 611(11):543-4, 2009. PMID: 19400305.
12. Ren Z, Mao X, Mertens C, Krishnaraj R, Qin J, Mandal PK, Romanowski MJ, McMurray JS, Chen X. Crystal structure of unphosphorylated STAT3 core fragment. Biochem Biophys Res Commun 374(1):1-5, 9/12/2008. e-Pub 4/21/2008. PMID: 18433722.
13. Coleman DR IV, Kaluarachchi K, Ren Z, Chen X, McMurray JS. Solid phase synthesis of phosphopeptides incorporating 2,2-dimethyloxazolidine pseudoproline analogues: evidence for trans Leu-Pro peptide bonds in Stat3 inhibitors. Int. J. Pept. Res. Ther. 14(1):1-9, 3/2008.
14. Robertson FM, Simeone AM, Mazumdar A, Shah AH, McMurray JS, Ghosh S, Cristofanilli M. Molecular and Pharmacological Blockade of The EP4 Receptor Selectively Inhibits Both Proliferation and Invasion of Human Inflammatory Breast Cancer Cells. J Exp Ther Oncol 7(4):299-312, 2008. PMID: 19227010.
15. Mandal PK, McMurray JS. Pd-C-induced catalytic transfer hydrogenation with triethylsilane. J Org Chem 72(17):6599-601, 8/2007. e-Pub 7/2007. PMID: 17630799.
16. Mandal PK, Heard PA, Ren Z, Chen X, McMurray JS. Solid-phase synthesis of Stat3 inhibitors incorporating O-carbamoylserine and O-carbamoylthreonine as glutamine mimics. Bioorg Med Chem Lett 17(3):654-6, 2/1/2007. e-Pub 11/6/2006. PMCID: PMC2676682.
17. Mandal PK, Kaluarachchi KK, Ogrin D, Bott SG, McMurray JS. An efficient synthesis of the constrained peptidomimetic 2-oxo-3-(N-9-fluorenyloxycarbonylamino)-1-azabicyclo[4.3.0]nonane-9-carbox ylic acid from pyroglutamic acid. J Org Chem 70(24):10128-31, 11/25/2005. PMID: 16292854.
18. Coleman DR, Ren Z, Mandal PK, Cameron AG, Dyer GA, Muranjan S, Campbell M, Chen X, McMurray JS. Investigation of the binding determinants of phosphopeptides targeted to the SRC homology 2 domain of the signal transducer and activator of transcription 3. Development of a high-affinity peptide inhibitor. J Med Chem 48(21):6661-70, 10/20/2005. PMID: 16220982.
19. Mandal PK, Cabell LA, McMurray, JS. The Synthesis of "Tyrosyl" Peptidomimetics by Acid-Catalysed N(1)-C(4) Ring Opening of 4-(4¢-Hydroxyphenyl)-azetidine-2-ones. Tetrahedron Letters 46:3715-3718, 2005.

Grant & Contract Support

Title: Inhibiting phosphoinositide-3-kinase-growth factor/cytokine complex formation
Funding Source: NIH/NCI
Role: Principal Investigator
Duration: 7/1/2014 - 6/30/2016
 
Title: Stat6 Inhibitors for the Treatment of Asthma
Funding Source: The American Asthma Foundation
Role: Principal Investigator
Duration: 7/1/2011 - 6/30/2014
 
Title: Beta Adrenergic Receptor Structure and Desensitization
Funding Source: NIH/NIGMS
Role: Co-Investigator
Principal Investigator: Richard Clark
Duration: 9/1/2009 - 8/31/2012
 
Title: Development of GRK5-beta2AR protein-protein interaction antagonists
Funding Source: John S. Dunn Gulf Coast Consortium for Chemical Genomics, RA Welch Foundation Chemistry and Biology Collaborative Grants
Role: Principal Investigator
Duration: 9/2008 - 8/2009
 
Title: NMR Shared Resource Facility
Funding Source: NMR Shared Resource
Role: Director
Duration: 7/1/2008 - 6/30/2013

Last updated: 8/9/2013