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Terrence R. Burke Jr., Ph.D.

Terrence R. Burke Jr., Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Senior Investigator
Chemical Biology Laboratory
Head, Bioorganic Chemistry Section

RESEARCH SUMMARY

Dr. Burke utilizes bioorganic and medicinal chemistry to prepare new biologically-active molecules, with an emphasis on peptides and peptide mimetics. His recent work has dealt with the development of inhibitors directed against phosphor-dependent protein-protein interactions, HIV-1 integrase and protein-tyrosine phosphatases. He is also engaged in developing antibody-drug conjugates. Link to additional information about Dr. Burke's research.

Areas of Expertise

Bioorganic and Medicinal Chemistry
Peptide and Peptide Mimetic Chemistry 
Inhibitors of Phospho-Dependent Protein-Protein Interactions (PPIs)
HIV Integrase Inhibitors
Antibody-Drug Conjugates (ADCs)

Publications

Selected Key Publications

Structural basis for strand-transfer inhibitor binding to HIV intasomes

Passos DO, Li M, Jóźwik IK, Zhao XZ, Santos-Martins D, Yang R, Smith SJ, Jeon Y, Forli S, Hughes SH, Burke TR Jr, Craigie R, Lyumkis D
Science. 367(6479): 810-14, 2020. [ Journal Article ]

Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening

Lountos GT, Zhao XZ, Kiselev E, Tropea JE, Needle D, Pommier Y, Burke TR, Waugh DS
Nucleic Acids Res. 47(19): 10134-50, 2019. [ Journal Article ]

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

Lu X, Nowicka U, Sridharan V, Liu F, Randles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ
Nat Commun.. 8: 15540, 2017. [ Journal Article ]

A route to imidazolium-containing phosphopeptide macrocycles

Qian, W.-J.; Park, J.-E.; Grant, R.; Lai, C.C.; Kelley, J.A.; Yaffe, M.B.; Lee, K.S.; Burke, T.R., Jr.
Biopolymers Peptide Science. 104: 663-673, 2015. [ Journal Article ]

HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant integrases

Zhao, X.Z.; Smith, S.J.; Maskell, D.P.; Metifiot, M.; Pye, V.E.; Fesen, K.; Marchand, C.; Pommier, Y.; Cherepanov, P.; Hughes, S.H.; Burke, T.R., Jr
ACS Chemical Biology. 11: 1074-1081, 2016. [ Journal Article ]

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Team

Ramesh Chingle
Postdoctoral Fellow (Visiting)
Ramesh Chingle, Ph.D.
Kedika
Postdoctoral Fellow (Visiting)
Samanthreddy Kedika , Ph.D.
Mahajan
Postdoctoral Fellow (Visiting)
Pankaj Mahajan, Ph.D.
Steven Smith
Senior Research Assistant
Steven J Smith, Ph.D.
POSTDOCTORAL FELLOW (VISITING)
Anand Kulkarni, Ph.D.

Covers

RSC-Chemical Biology cover

Affinity enhancement of polo-like kinase 1 polo box domain-binding ligands by a bivalent approach using a covalent kinase-binding component

Published Date

The polo-like kinase 1 (Plk1) is an important cell cycle regulator that is recognized as a target molecule
for development of anti-cancer agents. Plk1 consists of a catalytic kinase domain (KD) and a polo-box
domain (PBD), which engages in protein–protein interactions (PPIs) essential to proper Plk1 function.
Recently, we developed extremely high-affinity PBD-binding inhibitors based on a bivalent approach
using the Plk1 KD-binding inhibitor, BI2536, and a PBD-binding peptide. Certain of the resulting bivalent
constructs exhibited more than 100-fold Plk1 affinity enhancement relative to the best monovalent
PBD-binding ligands. Herein, we report an extensive investigation of bivalent ligands that utilize the nonselective
kinase inhibitor Wortmannin as a Plk1 KD-binding component. We found that bivalent ligands
incorporating Wortmannin demonstrated affinity enhancements that could be similar to what we had
obtained with BI2536 and that they could tightly bind to the protein. This suggests that these tight
binding ligands might be useful for structural analysis of full-length Plk1.

Citation

Kohei Tsuji, Hirokazu Tamamura and Terrence R. Burke Jr.

RSC Chemical Biology, 2024, 5, 721-728

RSCCB cover

Identification of multidentate tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors that simultaneously access the DNA, protein and catalytic-binding sites by oxime diversification

Published Date

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family that can downregulate the anticancer effects of the type I topoisomerase (TOP1) inhibitors by hydrolyzing the 30-phosphodiester bond between DNA and the TOP1 residue Y723 in the critical stalled intermediate that is the foundation of TOP1 inhibitor mechanism of action. Thus, TDP1 antagonists are attractive as potential enhancers of TOP1 inhibitors. However, the open and extended nature of the TOP1–DNA substratebinding region has made the development of TDP1 inhibitors extremely challenging. In this study, starting from our recently identified small molecule microarray (SMM)-derived TDP1-inhibitory imidazopyridine motif, we employed a click-based oxime protocol to extend the parent platform into the DNA and TOP1 peptide substrate-binding channels. We applied one-pot Groebke Blackburn–Bienayme multicomponent reactions (GBBRs) to prepare the needed aminooxy-containing substrates. By reacting these precursors with approximately 250 aldehydes in microtiter format, we screened a library of nearly 500 oximes for their TDP1 inhibitory potencies using an in vitro florescence-based catalytic assay. Select hits were structurally explored as their triazole- and ether-based isosteres. We obtained crystal structures of two of the resulting inhibitors bound to the TDP1 catalytic domain. The structures reveal that the inhibitors form hydrogen bonds with the catalytic His-Lys-Asn triads (‘‘HKN’’ motifs: H263, K265, N283 and H493, K495, N516), while simultaneously extending into both the substrate DNA and TOP1 peptide-binding grooves. This work provides a structural model for developing multivalent TDP1 inhibitors capable of binding in a tridentate fashion with a central component situated within the catalytic pocket and extensions that project into both the DNA and TOP1 peptide substrate-binding regions.

Citation

Xue Zhi Zhao, Wenjie Wang, George T. Lountos, Evgeny Kiselev, Joseph E. Trope, Danielle Needle, Yves Pommier and Terrence R. Burke, Jr. 

RSC Chemical Biology, 2023, 4, 334-343

molecule model in a lab

Synthetic Approaches to a Key Pyridone-carboxylic Acid Precursor Common to the HIV‑1 Integrase Strand Transfer Inhibitors Dolutegravir, Bictegravir, and Cabotegravir

Published Date

Dolutegravir (DTG), Bictegravir (BIC), and Cabotegravir (CAB) are the second-generation integrase strand transfer inhibitors (INSTIs) that have been FDA-approved for the treatment of HIV-1 infection. Preparation of these INSTIs utilizes the common intermediate 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (6). Presented herein is a literature and patent review of synthetic routes used to access the pharmaceutically important intermediate 6. The review highlights the ways in which small fine-tuned synthetic modifications have been used to achieve good yields and regioselectivity of ester hydrolysis.

Citation

Pankaj S. Mahajan and Terrence R. Burke, Jr.

Org. Process Res. Dev. 2023, 27, 5, 847–853

RSC

Development of ultra-high affinity bivalent ligands targeting the polo-like kinase 1

Published Date

Back Cover

Showcasing research from the Burke Group in the Chemical Biology Laboratory, NCI, NIH, USA. Development of ultra-high affinity bivalent ligands targeting the polo-like kinase 1 Bivalent ligands are described that are designed to access both the catalytic kinase domain (KD) and the polo-box domain (PBD) of the polo-like kinase 1 (Plk1). Exceptionally high binding affinities were retained even with minimal linkers between KD and PBD-binding components. This potentially suggests spatial orientation of the KD and PBD consistent with simultaneous occupancy. Such an orientation could have important implications for Plk1 structure-function.

Citation

Kohei Tsuji, David Hymel, Buyong Ma, Hirokazu Tamamura, Ruth Nussinov and Terrence R. Burke Jr.

RSC Chemical Biology, 2022, 3 , 1111-1120.

OBC

Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles

Published Date

Targeting protein – protein interactions (PPIs) has emerged as an important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1(Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phosphor dependent PPI antagonists can be significantly enhanced by taking advantage of interactions in both the phospho-binding site and hidden “cryptic” pockets that may be revealed on ligand binding. In our current paper, we describe the design and synthesis of macrocyclic peptide mimetics directed against the Plk1 PBD, which are characterized by a new glutamic acid analog that simultaneously serves as a ring-closing junction that provides accesses to a cryptic binding pocket, while at the same time achieving proper orientation of a phosphothreonine (pT) residue for optimal interaction in the signature phospho-binding pocket. Macrocycles prepared with this new amino acid analog introduce additional hydrogen-bonding interactions not found in the open-chain linear parent peptide. It is noteworthy that this new glutamic acid-based amino acid analog represents the first example of extremely high affinity ligands where access to the cryptic pocket from the pT-2 position is made possible with a residue that is not based on histidine. The concepts employed in the design and synthesis of these new macrocyclic peptide mimetics should be useful for further studies directed against the Plk1 PBD and potentially for ligands directed against other PPI targets.

This article can be accessed directly from the Royal Society of Chemistry at Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles - Organic & Biomolecular Chemistry (RSC Publishing)(link is external)

Citation

David Hymel, Kohei Tsuji, Robert A. Grant, Ramesh M. Chingle, Dominique L. Kunciw, Michael B. Yaffe and Terrence R. Burke, Jr.*

Organic & Biomolecular Chemistry, 202119, 7843-7854.

ACSID

HIV‑1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants

Published Date

The inside cover shows INSTIs bound to HIV-1 IN.  Compound 5j (magenta) was docked onto the structures of 4d (yellow) and BIC (green) bound to the active site of HIV-1 IN; the surface of IN is shown in white. The surface envelope of the unprocessed 3′ end of the vDNA is shown as brown mesh. Ordered water molecules bound to the active site of IN in the absence of a bound INSTI are shown in cyan.

Abstract: Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker. The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants. However, because there are mutations that reduce the potency of all the available INSTIs, new and better compounds are needed. Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3′-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants. We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold. One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested. Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

Citation

Steven J. Smith, Xue Zhi Zhao, Dario Oliveira Passos, Valerie E. Pye, Peter Cherepanov, Dmitry LyumkisTerrence R. Burke, Jr., and Stephen H. Hughes*

ACS Infectious Diseases, 20217, 1469-1482

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