“Addition” and “Subtraction”: Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors

Chen, Xin; Giraldes, John; Sprague, Elizabeth R.; Shakya, Subarna; Chen, Zhuoliang; Wang, Yaping; Joud, Carol; Mathieu, Simon; Chen, Christine Hiu-Tung; Straub, Christopher; Duca, Jose; Hurov, Kristen; Yuan, Yanqiu; Shao, Wenlin; Touré, B. Barry

doi:10.1021/acs.jmedchem.7b00033

Title: “Addition” and “Subtraction”: Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors

Journal Article · Fri Feb 10 00:00:00 EST 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b00033· OSTI ID:1404989

^[1]; Giraldes, John ^[1]; Sprague, Elizabeth R. ^[1]; Shakya, Subarna ^[1]; Chen, Zhuoliang ^[1]; Wang, Yaping ^[1]; Joud, Carol ^[1]; Mathieu, Simon ^[1]; Chen, Christine Hiu-Tung ^[1]; Straub, Christopher ^[1]; Duca, Jose ^[1]; Hurov, Kristen ^[1]; Yuan, Yanqiu ^[1]; Shao, Wenlin ^[1]; Touré, B. Barry ^[1]

Novartis Inst. for BioMedical Research, Inc., Cambridge, MA (United States)

While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Furthermore, reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

OSTI ID:: 1404989

Journal Information:: Journal of Medicinal Chemistry, Vol. 60, Issue 5; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 5 works

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References (16)

Rational Approaches to Improving Selectivity in Drug Design Huggins, David J.; Sherman, Woody; Tidor, Bruce Journal of Medicinal Chemistry, Vol. 55, Issue 4 https://doi.org/10.1021/jm2010332	journal	January 2012
Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators Zhan, Peng; Itoh, Yukihiro; Suzuki, Takayoshi Journal of Medicinal Chemistry, Vol. 58, Issue 19 https://doi.org/10.1021/acs.jmedchem.5b00229	journal	July 2015
Substrate Specificity and Activity Regulation of Protein Kinase MELK Beullens, Monique; Vancauwenbergh, Sadia; Morrice, Nick Journal of Biological Chemistry, Vol. 280, Issue 48 https://doi.org/10.1074/jbc.M507274200	journal	December 2005
Maternal Embryonic Leucine Zipper Kinase/Murine Protein Serine-Threonine Kinase 38 Is a Promising Therapeutic Target for Multiple Cancers Gray, Daniel; Jubb, Adrian M.; Hogue, Deborah Cancer Research, Vol. 65, Issue 21 https://doi.org/10.1158/0008-5472.CAN-04-4531	journal	November 2005
Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis Komatsu, Masato; Yoshimaru, Tetsuro; Matsuo, Taisuke International Journal of Oncology, Vol. 42, Issue 2 https://doi.org/10.3892/ijo.2012.1744	journal	December 2012
Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase Johnson, Christopher N.; Berdini, Valerio; Beke, Lijs ACS Medicinal Chemistry Letters, Vol. 6, Issue 1 https://doi.org/10.1021/ml5001245	journal	May 2014
Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase Johnson, Christopher N.; Adelinet, Christophe; Berdini, Valerio ACS Medicinal Chemistry Letters, Vol. 6, Issue 1 https://doi.org/10.1021/ml5001273	journal	May 2014
Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight Touré, B. Barry; Giraldes, John; Smith, Troy Journal of Medicinal Chemistry, Vol. 59, Issue 10 https://doi.org/10.1021/acs.jmedchem.6b00052	journal	May 2016
Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design Blanc, Javier; Geney, Raphael; Menet, Christel Anti-Cancer Agents in Medicinal Chemistry, Vol. 13, Issue 5 https://doi.org/10.2174/1871520611313050008	journal	May 2013
Ins and Outs of Kinase DFG Motifs Treiber, Daniel K.; Shah, Neil P. Chemistry & Biology, Vol. 20, Issue 6 https://doi.org/10.1016/j.chembiol.2013.06.001	journal	June 2013
Comprehensive analysis of kinase inhibitor selectivity Davis, Mindy I.; Hunt, Jeremy P.; Herrgard, Sanna Nature Biotechnology, Vol. 29, Issue 11 https://doi.org/10.1038/nbt.1990	journal	October 2011
Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation Zuccotto, Fabio; Ardini, Elena; Casale, Elena Journal of Medicinal Chemistry, Vol. 53, Issue 7 https://doi.org/10.1021/jm901443h	journal	April 2010
A Novel Mode of Gleevec Binding Is Revealed by the Structure of Spleen Tyrosine Kinase Atwell, Shane; Adams, Jason M.; Badger, John Journal of Biological Chemistry, Vol. 279, Issue 53 https://doi.org/10.1074/jbc.M409792200	journal	December 2004
Relationships between Molecular Complexity, Biological Activity, and Structural Diversity Schuffenhauer, Ansgar; Brown, Nathan; Selzer, Paul Journal of Chemical Information and Modeling, Vol. 46, Issue 2 https://doi.org/10.1021/ci0503558	journal	March 2006
Generation of a Set of Simple, Interpretable ADMET Rules of Thumb Gleeson, M. Paul Journal of Medicinal Chemistry, Vol. 51, Issue 4 https://doi.org/10.1021/jm701122q	journal	February 2008
What is Cooperativity? Hunter, Christopher A.; Anderson, Harry L. Angewandte Chemie International Edition, Vol. 48, Issue 41 https://doi.org/10.1002/anie.200902490	journal	September 2009

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Structure-based discovery of new maternal embryonic leucine zipper kinase inhibitors Zhou, Shu; Li, Guo-Bo; Luo, Lin Organic & Biomolecular Chemistry, Vol. 16, Issue 9 https://doi.org/10.1039/c7ob02344h	journal	January 2018

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Title: “Addition” and “Subtraction”: Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors

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