Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes

Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes

Qian Zhao†‡⊥, Xiaohu Ouyang†⊥, Xiaobo Wan†, Ketan S. Gajiwala∥, John C. Kath∥, Lyn H. Jones§, Alma L. Burlingame‡, and Jack Taunton*†
†Department of Cellular and Molecular Pharmacology and ‡Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States
§ Medicine Design, Pfizer, Cambridge, Massachusetts 02139, United States
∥ Worldwide Research and Development, Pfizer, San Diego, California 92121, United States
J. Am. Chem. Soc., 2017, 139 (2), pp 680–685
DOI: 10.1021/jacs.6b08536
Publication Date (Web): January 4, 2017
Copyright © 2017 American Chemical Society

Covalent Modulators of the Vacuolar ATPase

Ying-Chu Chen, Keriann M. Backus, Maria Merkulova, Christina Yang, Dennis Brown, Benjamin F. Cravatt, and Chao Zhang

J. Am. Chem. Soc., 2017, 139 (2), pp 639–642

DOI: 10.1021/jacs.6b12511

What Do Reactive Fragments Actually Do in Cells?

What Do Reactive Fragments Actually Do in Cells?
Angewante Chemie
Prof. Dr. Oliver Plettenburg
DOI: 10.1002/anie.201607914

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