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https://www.readbyqxmd.com/read/28287083/brigatinib-combined-with-anti-egfr-antibody-overcomes-osimertinib-resistance-in-egfr-mutated-non-small-cell-lung-cancer
#1
Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance...
March 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28286128/deacylation-mechanism-by-sirt2-revealed-in-the-1-sh-2-o-myristoyl-intermediate-structure
#2
Yi Wang, Yi Man Eva Fung, Weizhe Zhang, Bin He, Matthew Wai Heng Chung, Jing Jin, Jing Hu, Hening Lin, Quan Hao
Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl lysine peptide-based inhibitor and carba-NAD or NAD. Interestingly, by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the previously established intermediates I and II...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28285521/exploring-covalent-allosteric-inhibition-of-antigen-85c-from-mycobacterium-tuberculosis-by-ebselen-derivatives
#3
Christopher M Goins, Steven J Dajnowicz, Sandeep Thanna, Steven J Sucheck, Jerry Matthew Parks, Donald R Ronning
Previous studies identified ebselen as a potent in vitro and in vivo inhibitor of the Mycobacterium tuberculosis (Mtb) antigen 85 (Ag85) complex, comprising three homologous enzymes required for the biosynthesis of the mycobacterial cell wall. In this study, the Mtb Ag85C enzyme was co-crystallized with azido and adamantyl ebselen derivatives, resulting in two crystallographic structures of 2.01 and 1.30 Å resolution, respectively. Both structures displayed the anticipated covalent modification of the solvent accessible, non-catalytic Cys209 residue forming a selenenylsulfide bond...
March 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28282122/discovery-of-r-1-3-4-amino-3-3-chloro-4-pyridin-2-ylmethoxy-phenyl-1h-pyrazolo-3-4-d-pyrimidin-1-yl-piperidin-1-yl-prop-2-en-1-one-chmfl-egfr-202-as-a-novel-irreversible-egfr-mutants-kinase-inhibitor-with-a-distinct-binding-mode
#4
Aoli Wang, Xixiang Li, Hong Wu, Fengming Zou, Xiao-E Yan, Cheng Chen, Chen Hu, Kailin Yu, Wenchao Wang, Peng Zhao, Jiaxin Wu, Ziping Qi, Wei Wang, Beilei Wang, Li Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Jing Liu, Qingsong Liu
Based on Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered a novel EGFR inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02), especially it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-Helix-out" inactive EGFR conformation...
March 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28272868/mechanism-based-inhibition-of-the-mycobacterium-tuberculosis-branched-chain-aminotransferase-by-d-and-l-cycloserine
#5
Tathyana Mar Amorim Franco, Lorenza Favrot, Olivia Vergnolle, John S Blanchard
The branched-chain aminotransferase is a pyridoxal 5'-phosphate (PLP)-dependent enzyme responsible for the final step in the biosynthesis of all three branched-chain amino acids, L-leucine, L-isoleucine and L-valine, in bacteria. We have investigated the mechanism of inactivation of the branched-chain aminotransferase from Mycobacterium tuberculosis (MtIlvE) by D- and L-cycloserine. D-cycloserine is currently used only in the treatment of multidrug-drug resistant tuberculosis. Our results show a time- and concentration-dependent inactivation of MtIlvE by both isomers, with L-cycloserine being a 40-fold better inhibitor of the enzyme...
March 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28271476/%C3%AE-2-macroglobulins-structure-and-function
#6
Irene Garcia-Ferrer, Aniebrys Marrero, F Xavier Gomis-Rüth, Theodoros Goulas
α2-macroglobulins are broad-spectrum endopeptidase inhibitors, which have to date been characterised from metazoans (vertebrates and invertebrates) and Gram-negative bacteria. Their structural and biochemical properties reveal two related modes of action: the "Venus flytrap" and the "snap-trap" mechanisms. In both cases, peptidases trigger a massive conformational rearrangement of α2-macroglobulin after cutting in a highly flexible bait region, which results in their entrapment. In some homologs, a second action takes place that involves a highly reactive β-cysteinyl-γ-glutamyl thioester bond, which covalently binds cleaving peptidases and thus contributes to the further stabilization of the enzyme:inhibitor complex...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28267172/discovery-of-a-new-class-of-highly-potent-necroptosis-inhibitors-targeting-the-mixed-lineage-kinase-domain-like-protein
#7
Bo Yan, Lei Liu, Shaoqiang Huang, Yan Ren, Huayi Wang, Zhenglin Yao, Lin Li, She Chen, Xiaodong Wang, Zhiyuan Zhang
We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target...
March 7, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28253433/ubfluor-a-fluorescent-thioester-to-monitor-hect-e3-ligase-catalysis
#8
David T Krist, Peter K Foote, Alexander V Statsyuk
HECT E3 ubiquitin ligases (∼28 are known) are associated with many phenotypes in eukaryotes and are important drug targets. However, assays used to screen for small molecule inhibitors of HECT E3s are complex and require ATP, Ub, E1, E2, and HECT E3 enzymes, producing three covalent thioester enzyme intermediates E1∼Ub, E2∼Ub, and HECT E3∼Ub (where ∼ indicates a thioester bond), and mixtures of polyubiquitin chains. To reduce the complexity of the assay, we developed a novel class of fluorescent probes, UbFluor, that act as mechanistically relevant pseudosubstrates of HECT E3s...
March 2, 2017: Current Protocols in Chemical Biology
https://www.readbyqxmd.com/read/28253193/structural-and-functional-insight-into-pan-endopeptidase-inhibition-by-%C3%AE-2-macroglobulins
#9
Theodoros Goulas, Irene Garcia-Ferrer, Aniebrys Marrero, Laura Marino-Puertas, Stephane Duquerroy, F Xavier Gomis-Rüth
Peptidases must be exquisitely regulated to prevent erroneous cleavage and one control is provided by protein inhibitors. These are usually specific for particular peptidases or families and sterically block the active-site cleft of target enzymes using lock-and-key mechanisms. In contrast, members of the +1400-residue multi-domain α2-macroglobulin inhibitor family (α2Ms) are directed against a broad spectrum of endopeptidases of disparate specificities and catalytic types, and they inhibit their targets without disturbing their active sites...
March 2, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28242208/interplay-between-sirt1-and-hepatitis-b-virus-x-protein-in-the-activation-of-viral-transcription
#10
Jian-Jun Deng, Ka-Yiu Edwin Kong, Wei-Wei Gao, Hei-Man Vincent Tang, Vidyanath Chaudhary, Yun Cheng, Jie Zhou, Chi-Ping Chan, Danny Ka-Ho Wong, Man-Fung Yuen, Dong-Yan Jin
Hepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD(+)-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription...
February 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28240180/structure-based-virtual-screening-approaches-in-kinase-directed-drug-discovery
#11
Dávid Bajusz, György G Ferenczy, György M Keserű
Protein kinases are one of the most targeted protein families in current drug discovery pipelines. They are implicated in many oncological, inflammatory, CNS-related and other clinical indications. Virtual screening is a computational technique with a diverse set of available tools that has been shown many times to provide novel starting points for kinase-directed drug discovery. This review starts with a concise overview of the function, structural features and inhibitory mechanisms of protein kinases. In addition to briefly reviewing practical aspects of structure-based virtual screenings, we discuss several case studies to illustrate the state of the art in the virtual screening for type I, type II, allosteric (type III-V) and covalent (type VI) kinase inhibitors...
February 24, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28237762/synthesis-sar-and-molecular-docking-study-of-novel-non-%C3%AE-lactam-inhibitors-of-tem-type-%C3%AE-lactamase
#12
Roman L Antipin, Daria A Beshnova, Rostislav A Petrov, Anna S Shiryaeva, Irina P Andreeva, Vitaly G Grigorenko, Maya Yu Rubtsova, Alexander G Majouga, Victor S Lamzin, Alexey M Egorov
The novel classes of acylated phenoxyanilide and thiourea compounds were investigated for their ability to inhibit TEM type β-lactamase enzyme. Two compounds 4g and 5c reveal the inhibition potency in micromolar range and show their action by non-covalent binding in the vicinity of the TEM-171 active site. The structure activity relationship around carbon chain length and different substituents in ortho- and para-positions of acylated phenoxyanilide as well as molecular modelling study has been performed.
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28236590/potent-covalent-inhibitors-of-bacterial-urease-identified-by-activity-reactivity-profiling
#13
Katarzyna Macegoniuk, Rafał Kowalczyk, Anna Rudzińska, Mateusz Psurski, Joanna Wietrzyk, Łukasz Berlicki
Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range...
February 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28230989/development-of-the-first-generation-of-disulfide-based-subtype-selective-and-potent-covalent-pyruvate-dehydrogenase-kinase-1-pdk1-inhibitors
#14
Yifu Liu, Zuoquan Xie, Dan Zhao, Jin Zhu, Fei Mao, Shuai Tang, Hui Xu, Cheng Luo, Meiyu Geng, Min Huang, Jian Li
Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17 × 10(3) M(-1) s(-1)) and the cellular level (down to 0.1 μM)...
March 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28228478/an-engineered-tgf-%C3%AE-monomer-that-functions-as-a-dominant-negative-to-block-tgf-%C3%AE-signaling
#15
Sun Kyung Kim, Lindsey Barron, Cynthia S Hinck, Elyse M Petrunak, Kristin E Cano, Avinash Thangirala, Brian Iskra, Molly Brothers, Machell Vonberg, Belinda Leal, Blair Richter, Ravindra Kodali, Alex B Taylor, Shoucheng Du, Christopher O Barnes, Traian Sulea, Guillermo Calero, P John Hart, Matthew J Hart, Borries Demeler, Andrew P Hinck
The transforming growth factor beta isoforms, TGF-β1, -β2, and -β3 are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. In spite of the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor, TβRI, but dispensible for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor, TβRII, as an alternative therapeutic modality for blocking TGF-β signaling in humans...
February 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28225269/indazole-based-covalent-inhibitors-to-target-drug-resistant-epidermal-growth-factor-receptor
#16
Stefano Tomassi, Jonas Lategahn, Julian Engel, Marina Keul, Hannah L Tumbrink, Julia Ketzer, Thomas Mühlenberg, Matthias Baumann, Carsten Schultz-Fademrecht, Sebastian Bauer, Daniel Rauh
The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds...
March 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28225177/an-irreversible-inhibitor-of-hsp72-that-unexpectedly-targets-lysine-56
#17
Jonathan Pettinger, Yann-Vaï Le Bihan, Marcella Widya, Rob L M van Montfort, Keith Jones, Matthew D Cheeseman
The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition...
February 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28196299/activity-based-probes-for-the-ubiquitin-conjugation-deconjugation-machinery-new-chemistries-new-tools-and-new-insights
#18
REVIEW
David S Hewings, John A Flygare, Matthew Bogyo, Ingrid E Wertz
The reversible post-translational modification of proteins by ubiquitin and ubiquitin-like proteins regulates almost all cellular processes, by affecting protein degradation, localization, and complex formation. Deubiquitinases (DUBs) are proteases that remove ubiquitin modifications or cleave ubiquitin chains. Most DUBs are cysteine proteases, which makes them well suited for study by activity-based probes. These DUB probes report on deubiquitinase activity by reacting covalently with the active site in an enzyme-catalyzed manner...
February 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28193034/leveraging-gas-phase-fragmentation-pathways-for-improved-identification-and-selective-detection-of-targets-modified-by-covalent-probes
#19
Scott B Ficarro, Christopher M Browne, Joseph D Card, William M Alexander, Tinghu Zhang, Eunyoung Park, Randall McNally, Sirano Dhe-Paganon, Hyuk-Soo Seo, Ilaria Lamberto, Michael J Eck, Sara J Buhrlage, Nathanael S Gray, Jarrod A Marto
The recent approval of covalent inhibitors for multiple clinical indications has reignited enthusiasm for this class of drugs. As interest in covalent drugs has increased, so too has the need for analytical platforms that can leverage their mechanism-of-action to characterize modified protein targets. Here we describe novel gas phase dissociation pathways which yield predictable fragment ions during MS/MS of inhibitor-modified peptides. We find that these dissociation pathways are common to numerous cysteine-directed probes as well as the covalent drugs, Ibrutinib and Neratinib...
December 20, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/28186401/chemoproteomic-screening-of-covalent-ligands-reveals-uba5-as-a-novel-pancreatic-cancer-target
#20
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
February 15, 2017: ACS Chemical Biology
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