Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

Horton, John R.; Woodcock, Clayton B.; Chen, Qin; Liu, Xu; Zhang, Xing; Shanks, John; Rai, Ganesha; Mott, Bryan T.; Jansen, Daniel J.; Kales, Stephen C.; Henderson, Mark J.; Cyr, Matthew; Pohida, Katherine; Hu, Xin; Shah, Pranav; Xu, Xin; Jadhav, Ajit; Maloney, David J.; Hall, Matthew D.; Simeonov, Anton; Fu, Haian; Vertino, Paula M.; Cheng, Xiaodong

doi:10.1021/acs.jmedchem.8b01219

Title: Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

Journal Article · 02 November 2018 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.8b01219 · OSTI ID:1506493

Horton, John R. ^[1]; Woodcock, Clayton B. ^[2]; Chen, Qin ^[2]; Liu, Xu ^[3]; Zhang, Xing ^[2]; Shanks, John ^[3];

^[4]; Mott, Bryan T. ^[4]; Jansen, Daniel J. ^[4]; Kales, Stephen C. ^[4]; Henderson, Mark J. ^[4]; Cyr, Matthew ^[4]; Pohida, Katherine ^[4]; Hu, Xin ^[4]; Shah, Pranav ^[4]; Xu, Xin ^[4]; Jadhav, Ajit ^[4]; Maloney, David J. ^[4];

^[4]; Simeonov, Anton ^[4] more »

The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States); Emory Univ. School of Medicine, Atlanta, GA (United States)
The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
Emory Univ. School of Medicine, Atlanta, GA (United States)
National Inst. of Health, Rockville, MD (United States). National Center for Advancing Translational Sciences
Emory Univ., Atlanta, GA (United States)

The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. In this work we identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]- pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Cancer Prevention Research Institute of Texas (CPRIT); National Cancer Institute (NCI); National Institutes of Health (NIH)

OSTI ID:: 1506493

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 23 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (52)

A Mild and Selective Method for the Hydrolysis of Esters with Trimethyltin Hydroxide Nicolaou, K. C.; Estrada, Anthony A.; Zak, Mark Angewandte Chemie International Edition, Vol. 44, Issue 9 https://doi.org/10.1002/anie.200462207	journal	February 2005
Preparation of 2-, 4-, 5-, and 6-aminonicotinic acid tert-butyl esters Wright, Stephen W. Journal of Heterocyclic Chemistry, Vol. 49, Issue 2 https://doi.org/10.1002/jhet.799	journal	February 2012
A Systematic Review of Histone Lysine-Specific Demethylase 1 and Its Inhibitors: LSD1 AND ITS INHIBITORS Zheng, Yi-Chao; Ma, Jinlian; Wang, Zhiru Medicinal Research Reviews, Vol. 35, Issue 5 https://doi.org/10.1002/med.21350	journal	May 2015
Afatinib in advanced NSCLC: a profile of its use Deeks, Emma D.; Keating, Gillian M. Drugs & Therapy Perspectives, Vol. 34, Issue 3 https://doi.org/10.1007/s40267-018-0482-6	journal	February 2018
[10] Mechanism-based enzyme inactivators Silverman, Richard B. Methods in Enzymology, Vol. 249, p. 240-283 https://doi.org/10.1016/0076-6879(95)49038-8	book	January 1995
Modeling covalent-modifier drugs Awoonor-Williams, Ernest; Walsh, Andrew G.; Rowley, Christopher N. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1865, Issue 11 https://doi.org/10.1016/j.bbapap.2017.05.009	journal	November 2017
Synergistic cytotoxicity of afatinib and cetuximab against EGFR T790M involves Rab11-dependent EGFR recycling Watanuki, Zenta; Kosai, Hitomi; Osanai, Nanae Biochemical and Biophysical Research Communications, Vol. 455, Issue 3-4 https://doi.org/10.1016/j.bbrc.2014.11.003	journal	December 2014
Highly predictive and interpretable models for PAMPA permeability Sun, Hongmao; Nguyen, Kimloan; Kerns, Edward Bioorganic & Medicinal Chemistry, Vol. 25, Issue 3 https://doi.org/10.1016/j.bmc.2016.12.049	journal	February 2017
From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors Liang, Jun; Labadie, Sharada; Zhang, Birong Bioorganic & Medicinal Chemistry Letters, Vol. 27, Issue 13 https://doi.org/10.1016/j.bmcl.2017.05.016	journal	July 2017
Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer Muvarak, Nidal E.; Chowdhury, Khadiza; Xia, Limin Cancer Cell, Vol. 30, Issue 4 https://doi.org/10.1016/j.ccell.2016.09.002	journal	October 2016
Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells Roesch, Alexander; Vultur, Adina; Bogeski, Ivan Cancer Cell, Vol. 23, Issue 6 https://doi.org/10.1016/j.ccr.2013.05.003	journal	June 2013
Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1 Shi, Yujiang; Lan, Fei; Matson, Caitlin Cell, Vol. 119, Issue 7 https://doi.org/10.1016/j.cell.2004.12.012	journal	December 2004
RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone 3 Christensen, Jesper; Agger, Karl; Cloos, Paul A. C. Cell, Vol. 128, Issue 6 https://doi.org/10.1016/j.cell.2007.02.003	journal	March 2007
A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations Sharma, Sreenath V.; Lee, Diana Y.; Li, Bihua Cell, Vol. 141, Issue 1 https://doi.org/10.1016/j.cell.2010.02.027	journal	April 2010
Histone Demethylase RBP2 Is Critical for Breast Cancer Progression and Metastasis Cao, Jian; Liu, Zongzhi; Cheung, William K. C. Cell Reports, Vol. 6, Issue 5 https://doi.org/10.1016/j.celrep.2014.02.004	journal	March 2014
Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors Dalvi, Maithili P.; Wang, Lei; Zhong, Rui Cell Reports, Vol. 19, Issue 8 https://doi.org/10.1016/j.celrep.2017.04.077	journal	May 2017
Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds Horton, John R.; Liu, Xu; Gale, Molly Cell Chemical Biology, Vol. 23, Issue 7 https://doi.org/10.1016/j.chembiol.2016.06.006	journal	July 2016
Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells Tumber, Anthony; Nuzzi, Andrea; Hookway, Edward S. Cell Chemical Biology, Vol. 24, Issue 3 https://doi.org/10.1016/j.chembiol.2017.02.006	journal	March 2017
Targeting histone demethylases KDM5A and KDM5B in AML cancer cells: A comparative view Shokri, Gelareh; Doudi, Shaghayegh; Fathi-Roudsari, Mehrnoosh Leukemia Research, Vol. 68 https://doi.org/10.1016/j.leukres.2018.02.003	journal	May 2018
Histone Lysine Methylation Dynamics: Establishment, Regulation, and Biological Impact Black, Joshua C.; Van Rechem, Capucine; Whetstine, Johnathan R. Molecular Cell, Vol. 48, Issue 4 https://doi.org/10.1016/j.molcel.2012.11.006	journal	November 2012
Engineered Covalent Inactivation of TFIIH-Kinase Reveals an Elongation Checkpoint and Results in Widespread mRNA Stabilization Rodríguez-Molina, Juan B.; Tseng, Sandra C.; Simonett, Shane P. Molecular Cell, Vol. 63, Issue 3 https://doi.org/10.1016/j.molcel.2016.06.036	journal	August 2016
Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases Herr, Caitlyn Q.; Hausinger, Robert P. Trends in Biochemical Sciences, Vol. 43, Issue 7 https://doi.org/10.1016/j.tibs.2018.04.002	journal	July 2018
JARID1 Histone Demethylases: Emerging Targets in Cancer Harmeyer, Kayla M.; Facompre, Nicole D.; Herlyn, Meenhard Trends in Cancer, Vol. 3, Issue 10 https://doi.org/10.1016/j.trecan.2017.08.004	journal	October 2017
Inhibitors of Protein Methyltransferases and Demethylases Kaniskan, H. Ümit; Martini, Michael L.; Jin, Jian Chemical Reviews, Vol. 118, Issue 3 https://doi.org/10.1021/acs.chemrev.6b00801	journal	March 2017
Systematic Study of the Glutathione (GSH) Reactivity of N -Arylacrylamides: 1. Effects of Aryl Substitution Cee, Victor J.; Volak, Laurie P.; Chen, Yuping Journal of Medicinal Chemistry, Vol. 58, Issue 23 https://doi.org/10.1021/acs.jmedchem.5b01018	journal	November 2015
Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives Westaway, Susan M.; Preston, Alex G. S.; Barker, Michael D. Journal of Medicinal Chemistry, Vol. 59, Issue 4 https://doi.org/10.1021/acs.jmedchem.5b01537	journal	April 2015
Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4- d ]pyrimidin-4(3 H )-one Derivatives Westaway, Susan M.; Preston, Alex G. S.; Barker, Michael D. Journal of Medicinal Chemistry, Vol. 59, Issue 4 https://doi.org/10.1021/acs.jmedchem.5b01538	journal	April 2015
Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase Butler, Kyle V.; Ma, Anqi; Yu, Wenyu Journal of Medicinal Chemistry, Vol. 59, Issue 21 https://doi.org/10.1021/acs.jmedchem.6b01244	journal	October 2016
Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A Horton, John R.; Liu, Xu; Wu, Lizhen Journal of Medicinal Chemistry, Vol. 61, Issue 7 https://doi.org/10.1021/acs.jmedchem.8b00261	journal	March 2018
Noncryogenic I/Br−Mg Exchange of Aromatic Halides Bearing Sensitive Functional Groups Using i- PrMgCl−Bis[2-( N , N -dimethylamino)ethyl] Ether Complexes Wang, Xiao-jun; Sun, Xiufeng; Zhang, Li Organic Letters, Vol. 8, Issue 2 https://doi.org/10.1021/ol052704p	journal	January 2006
A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response Kruidenier, Laurens; Chung, Chun-wa; Cheng, Zhongjun Nature, Vol. 488, Issue 7411 https://doi.org/10.1038/nature11262	journal	July 2012
Inhibition of demethylases by GSK-J1/J4 Heinemann, Bo; Nielsen, Jesper Morten; Hudlebusch, Heidi Rye Nature, Vol. 514, Issue 7520 https://doi.org/10.1038/nature13688	journal	October 2014
Prolonged and tunable residence time using reversible covalent kinase inhibitors Bradshaw, J. Michael; McFarland, Jesse M.; Paavilainen, Ville O. Nature Chemical Biology, Vol. 11, Issue 7 https://doi.org/10.1038/nchembio.1817	journal	May 2015
Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling Smith, Geoffrey A.; Uchida, Kenji; Weiss, Arthur Nature Chemical Biology, Vol. 12, Issue 5 https://doi.org/10.1038/nchembio.2056	journal	March 2016
An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells Vinogradova, Maia; Gehling, Victor S.; Gustafson, Amy Nature Chemical Biology, Vol. 12, Issue 7 https://doi.org/10.1038/nchembio.2085	journal	May 2016
Structural analysis of human KDM5B guides histone demethylase inhibitor development Johansson, Catrine; Velupillai, Srikannathasan; Tumber, Anthony Nature Chemical Biology, Vol. 12, Issue 7 https://doi.org/10.1038/nchembio.2087	journal	May 2016
Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1 Lin, W.; Cao, J.; Liu, J. Proceedings of the National Academy of Sciences, Vol. 108, Issue 33 https://doi.org/10.1073/pnas.1110104108	journal	July 2011
Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases Horton, John R.; Engstrom, Amanda; Zoeller, Elizabeth L. Journal of Biological Chemistry, Vol. 291, Issue 6 https://doi.org/10.1074/jbc.M115.698449	journal	December 2015
Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function Horowitz, Scott; Trievel, Raymond C. Journal of Biological Chemistry, Vol. 287, Issue 50 https://doi.org/10.1074/jbc.R112.418574	journal	October 2012
Targeting of 5-aza-2′-deoxycytidine residues by chromatin-associated DNMT1 induces proteasomal degradation of the free enzyme Patel, Katan; Dickson, Jacqueline; Din, Shahida Nucleic Acids Research, Vol. 38, Issue 13 https://doi.org/10.1093/nar/gkq187	journal	March 2010
The Discovery of Histone Demethylases Shi, Y. G.; Tsukada, Y. -i. Cold Spring Harbor Perspectives in Biology, Vol. 5, Issue 12 https://doi.org/10.1101/cshperspect.a022335	journal	December 2013
Histone Lysine Demethylase Inhibitors Jambhekar, Ashwini; Anastas, Jamie N.; Shi, Yang Cold Spring Harbor Perspectives in Medicine, Vol. 7, Issue 1 https://doi.org/10.1101/cshperspect.a026484	journal	October 2016
Association between H3K4 methylation and cancer prognosis: A meta-analysis: H3K4 methylation and cancer prognosis Li, Simin; Shen, Luyan; Chen, Ke-Neng Thoracic Cancer, Vol. 9, Issue 7 https://doi.org/10.1111/1759-7714.12647	journal	May 2018
Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker Solca, Flavio; Dahl, Goeran; Zoephel, Andreas Journal of Pharmacology and Experimental Therapeutics, Vol. 343, Issue 2 https://doi.org/10.1124/jpet.112.197756	journal	August 2012
Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors Murai, J.; Huang, S. -y. N.; Das, B. B. Cancer Research, Vol. 72, Issue 21 https://doi.org/10.1158/0008-5472.CAN-12-2753	journal	October 2012
Bioluminescent High-Throughput Succinate Detection Method for Monitoring the Activity of JMJC Histone Demethylases and Fe(II)/2-Oxoglutarate-Dependent Dioxygenases Alves, Juliano; Vidugiris, Gediminas; Goueli, Said A. SLAS DISCOVERY: Advancing the Science of Drug Discovery, Vol. 23, Issue 3 https://doi.org/10.1177/2472555217745657	journal	December 2017
KDM5 histone demethylases repress immune response via suppression of STING Wu, Lizhen; Cao, Jian; Cai, Wesley L. PLOS Biology, Vol. 16, Issue 8 https://doi.org/10.1371/journal.pbio.2006134	journal	August 2018
Genetic basis of Parkinson's disease: inheritance, penetrance, and expression Gasser, Thomas The Application of Clinical Genetics https://doi.org/10.2147/TACG.S11639	journal	June 2011
Reversible Michael Additions: Covalent Inhibitors and Prodrugs H. Johansson, Martin Mini-Reviews in Medicinal Chemistry, Vol. 12, Issue 13 https://doi.org/10.2174/13895575112091330	journal	October 2012
The KDM5 family of histone demethylases as targets in oncology drug discovery Rasmussen, Peter Birk; Staller, Peter Epigenomics, Vol. 6, Issue 3 https://doi.org/10.2217/epi.14.14	journal	June 2014
DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge Castillo-Aguilera, Omar; Depreux, Patrick; Halby, Ludovic Biomolecules, Vol. 7, Issue 4 https://doi.org/10.3390/biom7010003	journal	January 2017
Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer Blair, Lauren P.; Cao, Jian; Zou, Mike Ran Cancers, Vol. 3, Issue 1 https://doi.org/10.3390/cancers3011383	journal	March 2011

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Inhibition
Inhibitors
Monomers
Organic compounds
Peptides and proteins

Title: Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

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