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Dr. Terry Burke



Dr. Terry Burke
Bioorganic Chemistry
301-846-5906

Research Summary

Bioorganic Medicinal Chemistry and the Modulation of Kinase-Dependent Signal Transduction

Pharmacological agents are being developed to modulate phospho-dependent cell signaling. Historically, our emphasis in this area has been on inhibitors of phosphotyrosyl (pTyr)-dependent binding interactions, which are mediated by src homology 2 (SH2) domains and on protein-tyrosine phosphatase (PTP) inhibitors. More recently, our efforts have focused on developing polo-like kinase 1 (Plk1) polo-box domain (PBD)-binding inhibitors. Central to all these efforts is the development phosphoamino acid surrogates that afford either increased stability toward enzymatic degradation, increased affinity or increased cellular uptake. In the SH2 domain area, we have collaborated with Dr. Donald Bottaro (CCR, NCI) to develop cell-permeable growth factor receptor-bound 2 (Grb2) antagonists as potential new therapeutics for a variety of erbB-2- and MET-dependent cancers, including breast cancer. For this work, we designed peptidomimetics as conformationally constrained analogs of natural Grb2 SH2 domain-bound pTyr-containing peptides. In related research, a series of new pTyr-mimicking amino acid analogs were prepared to enhance cell permeability. In the phosphatase area, our recent efforts have concerned the development of inhibitors of the Yersinia pestis phosphatase, YopH, which is a PTP required for infectivity of this potential bioterrorism agent. This work is being conducted as a collaboration with Drs. David Waugh (CCR, NCI) and Robert Ulrich (USAMRIID). Here we have used an oxime library-based approach guided by X-ray co-crystal structures of our inhibitors bound to YopH. In the Plk1 area, we currently have a significant effort underway to develop Plk1 PBD-binding antagonists. This work is being done in collaboration with Dr. Kyung Lee (CCR, NCI). Starting from a pentamer phosphothreonine (pThr) peptide derived from a cognate Plk1 substrate, we are designing and synthesizing peptides and peptide mimetics that contain modified amino acid analogs. We have arrived at agents with extremely high PBD-binding affinity, that have the ability to block division of cancer cells in culture. The goal of this work is to achieve compounds that can exert potent anticancer effects in animal tumor models.


In separate work, inhibitors of HIV integrase are being developed as potential anti-AIDS drugs. Lead inhibitor structures have initially been derived from several sources, including three-dimensional pharmacophore searching of the more than 250,000 compounds contained within the NCI's chemical repository. Promising compounds have been systematically explored through chemical synthesis of analogs to determine structure-activity relationships (SAR) responsible for integrase inhibition. Information generated in this fashion has been applied to the design and preparation of new analogs having higher potency, reduced collateral cytotoxicity, and greater antiviral protective effects in HIV-infected cells. In collaboration with Drs. Steve Hughes (CCR, NCI) and Yves Pommier (CCR, NCI) we have recently developed non-cytotoxic agents that exhibit anti-viral efficacies in cell culture models of HIV-1 infectivity that equal or exceed the potencies of current clinical IN inhibitors, while retaining greater efficacy against virus harboring major resistant mutant forms of IN. A third area of investigation concerns developing antibody-drug conjugates (ADCs) in collaboration with Dr. Christoph Rader, Scripps, Florida. This work is focused on designing and synthesizing new constructs for attaching drugs and targeting moieties to antibodies.

Research Tools

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PublicationsPatents
1 - 5 of 311 results

1)  Zhao XZ, Smith SJ, Métifiot M, Johnson BC, Marchand C, Pommier Y, Hughes SH, Burke TR.
Bicyclic 1-Hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-Containing HIV-1 Integrase Inhibitors Having High Antiviral Potency Against Cells Harboring Raltegravir-Resistant Integrase Mutants.
J. Med. Chem. 2014. [Journal]

2)  Qian WJ, Lai CC, Kelley JA, Burke TR.
Design and synthesis of N-FMoc-Thr[PO(OH)(OPOM)] for the preparation of peptides prodrugs containing phosphothreonine in fully protected form.
Chem. Biodiver. 2013. In Press. [Journal]

3)  Métifiot M, Maddali K, Johnson BC, Hare S, Smith SJ, Zhao XZ, Marchand C, Burke TR, Hughes SH, Cherepanov P, Pommier Y.
Activities, crystal structures and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase.
ACS Chem. Biol. 8: 209-217, 2013. [Journal]

4)  Hogan M, Bahta M, Cherry S, Lountos GT, Tropea JE, Zhao BM, Burke TR, Waugh DS, Ulrich RG.
Biomolecular Interactions of Small-molecule Inhibitors Affecting the YopH Protein Tyrosine Phosphatase.
Chem Biol Drug Des. 81: 323-333, 2013. [Journal]

5)  Qian WJ, Burke TR.
Design and synthesis of a reagent for solid-phase incorporation of the phosphothreonine mimetic (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) into peptides in a bio-reversible phosphonyl-bis-pivaloyloxymethyl (POM) prodrug form.
Amino Acids. 45: 1143-8, 2013. [Journal]

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