Wednesday, December 26, 2018

Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy

Med. Chem. Commun., 2018 
DOI: 10.1039/C8MD00566D

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as a effective linker for irreversible protein tethering.

Tuesday, December 25, 2018

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Matthias Gehringer and Stefan A. Laufer
Journal of Medicinal Chemistry 
DOI: 10.1021/acs.jmedchem.8b01153

Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting non-catalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant chemical strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of non-catalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads beyond α,β-unsaturated amides that were recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and case studies illustrating applications in medicinal chemistry and chemical biology.

Tuesday, December 11, 2018

A Chemoproteomic Strategy for Direct and Proteome-wide Covalent Inhibitor Target-site Identification

Christopher Michael BrowneBaishan JiangScott B FicarroZainab M DoctorJared Lee JohnsonJoseph D CardSindhu Carmen SivakumarenWilliam M AlexanderTomer YaronCharles Joseph MurphyNicholas P KwiatkowskiTinghu ZhangLewis C. CantleyNathanael S Gray, and Jarrod A. Marto

Journal of the American Chemical Society 2018
DOI: 10.1021/jacs.8b07911

Despite recent clinical successes for irreversible drugs, potential toxicities mediated by unpredictable modification of off-target cysteines represents a major hurdle for expansion of covalent drug programs. Understanding the proteome-wide binding profile of covalent inhibitors can significantly accelerate their development; however, current mass spectrometry strategies typically do not provide a direct, amino acid level readout of covalent activity for complex, selective inhibitors. Here we report the development of CITe-Id, a novel chemoproteomic approach that employs covalent pharmacologic inhibitors as enrichment reagents in combination with an optimized proteomic platform to directly quantify dose-dependent binding at cysteine-thiols across the proteome. CITe-Id analysis of our irreversible CDK inhibitor THZ1 identified dose-dependent covalent modification of several unexpected kinases, including a previously unannotated cysteine (C840) on the understudied kinase PKN3. These data streamlined our development of JZ128 as a new selective covalent inhibitor of PKN3. Using JZ128 as a probe compound, we identified novel potential PKN3 substrates, thus offering an initial molecular view of PKN3 cellular activity. CITe-Id provides a powerful complement to current chemoproteomic platforms to characterize the selectivity of covalent inhibitors, identify new, pharmacologically-addressable cysteine-thiols, and inform structure-based drug design programs.

Monday, December 3, 2018

Overview of Current Type I/II Kinase Inhibitors

Zheng Zhao, Philip E. Bourne

Research on kinase-targeting drugs has made great strides over the last 30 years and is attracting greater attention for the treatment of yet more kinase-related diseases. Currently, 42 kinase drugs have been approved by the FDA, most of which (39) are Type I/II inhibitors. Notwithstanding these advances, it is desirable to target additional kinases for drug development as more than 200 diseases, particularly cancers, are directly associated with aberrant kinase regulation and signaling. Here, we review the extant Type I/II drugs systematically to obtain insights into the binding pocket characteristics, the associated features of Type I/II drugs, and the mechanism of action to facilitate future kinase drug design and discovery. We conclude by summarizing the main successes and limitations of targeting kinase for the development of drugs.

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...