Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Paul A. Jackson, John C. Widen, Daniel A. Harki^* and Kay M. Brummond^*

Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States

Journal of Medicinal Chemistry

Publication Date (Web): December 20, 2016

DOI: 10.1021/acs.jmedchem.6b00788

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors

Balyn W. Zaro, Landon R. Whitby, Kenneth M. Lum, and Benjamin F. Cravatt*

The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, 10550 North Torrey Pines Road, La Jolla, California 92037, United States

J. Am. Chem. Soc., 2016, 138 (49), pp 15841–15844

DOI: 10.1021/jacs.6b10589

The use of a fumarate ester warhead is found to confer greater selectivity than a simple acrylamide warhead for inhibition of Bruton's Tyrosine Kinase (BTK).

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Tinghu Zhang, Nicholas Kwiatkowski, Calla M Olson, Sarah E Dixon-Clarke, Brian J Abraham, Ann K Greifenberg, Scott B Ficarro, Jonathan M Elkins, Yanke Liang, Nancy M Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L Greenleaf, Jarrod A Marto, Matthias Geyer, Alex N Bullock, Richard A Young & Nathanael S Gray

Nature Chemical Biology 12, 787–794 (2016)

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

doi: 10.1038/nchembio.2166

Covalent inhibitors that target lysine side chains

Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

Gizem Akçay, Matthew A Belmonte, Brian Aquila, Claudio Chuaqui, Alexander W Hird, Michelle L Lamb, Philip B Rawlins, Nancy Su, Sharon Tentarelli, Neil P Grimster & Qibin Su

Nature Chemical Biology (2016) doi:10.1038/nchembio.2174

Cysteinome: The first comprehensive database for proteins with targetable cysteine and their covalent inhibitors

• Sijin Wu^a, b, 
• Huizhe Luo (Howard)^a, 
• Haina Wang^a, 
• Weijie Zhao^b, 
• Qiwan Hu^a, 
• Yongliang Yang^a, , 

• ^a Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116023, PR China
• ^b School of Pharmacology, Dalian University of Technology, Dalian, 116023, PR China

doi: 10.1016/j.bbrc.2016.08.109

http://www.cysteinome.org/

Angewante Chemie Review: Targeted Covalent Inhibitors for Drug Design by Thomas Baille

Targeted Covalent Inhibitors for Drug Design

The current issue of Angewante Chemie includes and extensive review on pharmaceutical inhibitors by Prof. T. A. Baillie from the Department of Medicinal Chemistry at the University of Washington.

DOI: 10.1002/anie.201601091

Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3

Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3

Alvin Kung, Ying-Chu Chen, Marianne Schimpl, Feng Ni, Jianfa Zhu, Maurice Turner, Henrik Molina, Ross Overman, and Chao Zhang

Department of Chemistry and Loker Hydrocarbon Research Institute, and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, United States
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Building 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Proteomic Resource Center, The Rockefeller University, New York, New York 10065, United States
J. Am. Chem. Soc., 2016, 138 (33), pp 10554–10560
DOI: 10.1021/jacs.6b05483
*zhang.chao@usc.edu

10.1021/jacs.6b05483