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Covalent inhibitors

Kate L Wegener, Amy E McGrath, Nicholas E Dixon, Aaron J Oakley, Denis B Scanlon, Andrew D Abell, John Bruning
The human sliding clamp (PCNA) controls access to DNA for many proteins involved in DNA replication and repair. Proteins are recruited to the PCNA surface by means of a short, conserved peptide motif known as the PCNA-interacting protein box (PIP-box). Inhibitors of these essential protein-protein interactions may be useful as cancer therapeutics by disrupting DNA replication and repair in these highly proliferative cells. PIP-box peptide mimetics have been identified as a potentially rapid route to potent PCNA inhibitors...
June 19, 2018: Chemistry: a European Journal
Xuefeng Guo, Yiming Chen, Christopher T Seto
Parasites have developed a variety of strategies for invading hosts and escaping their immune response. A common mechanism by which parasites escape nitric oxide (NO) toxicity is the activation of host arginase. This activation leads to a depletion of l-arginine, which is the substrate for NO synthase, resulting in lower levels of NO and increased production of polyamines that are necessary for parasite growth and differentiation. For this reason, small molecule inhibitors for arginase show promise as new anti-parasitic chemotherapeutics...
June 14, 2018: Bioorganic & Medicinal Chemistry
Yukiko Kasai, Kousuke Sato, Shohei Utsumi, Satoshi Ichikawa
DNA cytosine 5-methyltransferase (DNMT) catalyzes the methylation at the C5 position of the cytosine residues in the CpG sequence. Aberrant DNA methylation patterns are found in cancer cells. Therefore, inhibition of human DNMT is an effective strategy for treating various cancers. The inhibitors of DNMT have an electron-deficient nucleobase because this group facilitates the attack by the catalytic Cys residue in DNMTs. Recently, our group has reported the synthesis and properties of mechanism-based modified nucleosides, 2-amino-4-halopyridine-C-nucleosides (dXP), as inhibitors of DNMT...
June 14, 2018: Chembiochem: a European Journal of Chemical Biology
Amanda M S Mattice, Isabelle A MacLean, Christine L Childers, Kenneth B Storey
Background: Pyruvate kinase (PK) is responsible for the final reaction in glycolysis. As PK is a glycolytic control point, the analysis of PK posttranslational modifications (PTM) and kinetic changes reveals a key piece of the reorganization of energy metabolism in an anoxia tolerant vertebrate. Methods: To explore PK regulation, the enzyme was isolated from red skeletal muscle and liver of aerobic and 20-hr anoxia-exposed red eared-slider turtles ( Trachemys scripta elegans )...
2018: PeerJ
Gun-Woo Lee, Jun Bum Park, Sung Yeon Park, Jieun Seo, Seung-Hyun Shin, Jong-Wan Park, Sang Jung Kim, Masatoshi Watanabe, Yang-Sook Chun
Neddylation is a cellular process that covalently conjugates substrate proteins with the small ubiquitin-like molecule NEDD8. As neddylation is required for fast turnover of proteins in proliferating cancer cells, the neddylation process is currently regarded as a potential target for cancer therapy. However, little is known about the role of neddylation in cancer invasion and metastasis. Unexpectedly, we here found that the neddylation blockade stimulates migration of lung cancer and glioblastoma cells. Mechanistically, C-CBL acts as the E3 ligase for neddylation of the proto-oncogene c-Src...
June 13, 2018: Oncogene
Expédite Yen-Pon, Bo Li, Marta Acebron-Garcia-de-Eulate, Céline Tomkiewicz-Raulet, John Dawson, Daniel Lietha, Margaret C Frame, Xavier Coumoul, Christiane Garbay, Mélanie Etheve-Quelquejeu, Huixiong Chen
Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase...
June 13, 2018: ACS Chemical Biology
Miriam P Koetzler, Kyle Robinson, Hong-Ming Chen, Mark Okon, Lawrence P McIntosh, Stephen G Withers
Understanding the detailed mechanisms of enzyme-catalyzed hydrolysis of the glycosidic bond is fundamentally important, not only to the design of tailored cost-efficient, stable and specific catalysts, but also to the development of specific glycoside hydro-lase inhibitors as therapeutics. Retaining glycosidases employ two key carboxylic acid residues, typically glutamic acids, in a double-displacement mechanism involving a covalent glycosyl-enzyme intermediate. One Glu functions as a nucleophile while the other acts as a general acid/base...
June 12, 2018: Journal of the American Chemical Society
Nilima A Vyas, Sushma B Singh, Avinash S Kumbhar, Dnyanesh S Ranade, Gulshan R Walke, Prasad P Kulkarni, Vinod Jani, Uddhavesh B Sonavane, Rajendra R Joshi, Srikanth Rapole
Two heteronuclear ruthenium(II)-platinum(II) complexes [Ru(bpy)2 (BPIMBp)PtCl2 ]2+ (3) and [Ru(phen)2 (BPIMBp)PtCl2 ]2+ (4), where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and BPIMBp = 1,4'-bis[(2-pyridin-2-yl)-1H-imidazol-1-ylmethyl]-1,1'-biphenyl, have been designed and synthesized from their mononuclear precursors [Ru(bpy)2 (BPIMBp)]2+ (1) and [Ru(phen)2 (BPIMBp)]2+ (2) as multitarget molecules for Alzheimer's disease (AD). The inclusion of the cis-PtCl2 moiety facilitates the covalent interaction of Ru(II) polypyridyl complexes with amyloid β (Aβ) peptide...
June 12, 2018: Inorganic Chemistry
Alen Albreht, Irena Vovk, Janez Mavri, Jose Marco-Contelles, Rona R Ramsay
Successful propargylamine drugs such as deprenyl inactivate monoamine oxidase (MAO), a target in multi-faceted approaches to prevent neurodegeneration in the aging population, but the chemical structure and mechanism of the irreversible inhibition are still debated. We characterized the covalent cyanine structure linking the multi-target propargylamine inhibitor ASS234 and the flavin adenine dinucleotide in MAO-A using a combination of ultra-high performance liquid chromatography, spectroscopy, mass spectrometry, and computational methods...
2018: Frontiers in Chemistry
Andrea Scarpino, Gyorgy G Ferenczy, György M Keserű
The increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity of covalent inhibitors. Here we compare the performance of six covalent docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro and MOE for reproducing experimental binding modes in an unprecedently large and diverse set of covalent complexes. It was found that 40 to 60% of the top scoring ligand poses are within 2.0 Å RMSD from the experimental binding mode. This rate showed program dependent increase and achieved 50% to 90% when the best RMSD among the top ten scoring poses was considered...
June 11, 2018: Journal of Chemical Information and Modeling
Haruka Nishimuta, Kimihiko Sato, Takao Watanabe, Masashi Yabuki
1. The purpose of the present study was to clarify the mechanism of DSP-1053 time-dependent inhibition (TDI) for CYP1A2. 2. DSP-1053 inhibited time- and concentration-dependently CYP1A2 activity in human liver microsomes even in a dilution assay. However, DSP-1053 was not metabolized by recombinant human CYP1A2. These findings indicate that the inhibitory effect of DSP-1053 on CYP1A2 does not follow a general mechanism-based inhibition because it didn't seem to be a suicide substrate. 3. In fact, CYP1A2 was not inhibited with DSP-1053 pre-incubation in recombinant human CYP1A2...
June 11, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Christian Goess, Christopher M Harris, Sara Murdock, Richard W McCarthy, Erik Sampson, Rachel Twomey, Suzanne Mathieu, Regina Mario, Matthew Perham, Eric R Goedken, Andrew J Long
OBJECTIVES: Bruton's Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. METHODS: ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production...
June 2, 2018: Modern Rheumatology
Gareth K Jennings, Mei-Hui Hsu, Lisa S Shock, Eric F Johnson, John C Hackett
Cytochrome P450 4B1 (4B1) functions in both xenobiotic and endobiotic metabolism. An ester linkage between Glu-310 in 4B1 and the 5-methyl group of heme facilitates preferential hydroxylation of terminal (ω) methyl groups of hydrocarbons (HCs) and fatty acids compared with ω-1 sites bearing weaker C-H bonds. This preference is retained albeit diminished 4-fold for the E310A mutant, but the reason for this is unclear. Here, a crystal structure of the E310A-octane complex disclosed that noncovalent interactions maintain heme deformation in the absence of the ester linkage...
June 1, 2018: Journal of Biological Chemistry
Jaya Pandey, Preeti Prajapati, Anubha Srivastava, Poonam Tandon, Kirti Sinha, Alejandro P Ayala, Arvind K Bansal
Febuxostat (FXT) is a urate-lowering drug and xanthine oxidase inhibitor which is used for the treatment of hyperuricemia and gout caused by increased levels of uric acid in the blood (hyperuricemia). The present study aims to provide deeper knowledge of the structural, vibrational spectroscopic and physiochemical properties of FXT based on monomeric and dimeric model with the aid of combination of experimental and computational methods. The conformational analysis of form Q has been done to predict the possible structure of unknown form A...
May 22, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Michael Forster, Apirat Chaikuad, Teodor Dimitrov, Eva Döring, Julia Holstein, Benedict-Tilman Berger, Matthias Gehringer, Kamran Ghoreschi, Susanne Müller, Stefan Knapp, Stefan A Laufer
Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable co-localization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3...
May 31, 2018: Journal of Medicinal Chemistry
Rupesh Vitthalrao Chikhale, Mahesh A Barmade, Prashant R Murumkar, Mange Ram Yadav
Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), a vital enzyme for cell wall synthesis plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium...
May 31, 2018: Journal of Medicinal Chemistry
Alexandru D Buhimschi, Haley A Armstrong, Momar Toure, Saul Jaime-Figueroa, Timothy L Chen, Amy M Lehman, Jennifer A Woyach, Amy J Johnson, John C Byrd, Craig M Crews
Inhibition of Bruton's tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Yet, more than 80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK...
May 31, 2018: Biochemistry
Orville A Pemberton, Xiujun Zhang, Derek A Nichols, Kyle DeFrees, Priyadarshini Jaishankar, Richard Bonnet, Jessie Adams, Lindsey N Shaw, Adam R Renslo, Yu Chen
CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived non-covalent inhibitor of CTX-M-9. Here, we present biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while exhibiting some low-level inhibition of other serine β-lactamases. Complex crystal structures with CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active site residues on the β3 strand...
May 29, 2018: Antimicrobial Agents and Chemotherapy
Alex F Herrera, Arturo Molina
Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs...
May 10, 2018: Clinical Lymphoma, Myeloma & Leukemia
Peng Zhao, Ming-Yu Yao, Su-Jie Zhu, Ji-Yun Chen, Cai-Hong Yun
Lung cancer is the leading cause of cancer deaths. Epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small cell lung cancers (NSCLCs), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the anti-EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib initially, but soon develop resistance to them in about half of the cases due to the emergence of the gatekeeper mutation T790M. The third-generation TKIs such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to the EGFR kinase through Cys 797, but ultimately lose their efficacy upon emergence of the C797S mutation that abolishes the covalent bonding...
July 20, 2018: Biochemical and Biophysical Research Communications
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