Adam Birkholz, David J. Kopecky, Laurie P. Volak, Michael D. Bartberger, Yuping Chen, Christopher M. Tegley, Tara Arvedson, John D. McCarter, Christopher Fotsch, and Victor J. CeeDOI: 10.1021/acs.jmedchem.0c00749
Saturday, October 24, 2020
Systematic Study of the Glutathione (GSH) Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution
Brooke X. C. Kwai, Annabelle J. Collins, Martin J. Middleditch, Jonathan Sperry, Ghader Bashiri and Ivanhoe K. H. Leung
RSC Med. Chem., 2020
Itaconate is a mammalian antimicrobial metabolite that inhibits the isocitrate lyases (ICLs) of Mycobacterium tuberculosis. Herein, we report that ICLs form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.
Friday, October 23, 2020
Hongyan Du, Junbo Gao, Gaoqi Weng, Junjie Ding, Xin Chai, Jinping Pang, Yu Kang, Dan Li, Dongsheng Cao, Tingjun Hou
Nucleic Acids Research, 2020, gkaa876,
Inhibitors that form covalent bonds with their targets have traditionally been considered highly adventurous due to their potential off-target effects and toxicity concerns. However, with the clinical validation and approval of many covalent inhibitors during the past decade, design and discovery of novel covalent inhibitors have attracted increasing attention. A large amount of scattered experimental data for covalent inhibitors have been reported, but a resource by integrating the experimental information for covalent inhibitor discovery is still lacking. In this study, we presented Covalent Inhibitor Database (CovalentInDB), the largest online database that provides the structural information and experimental data for covalent inhibitors. CovalentInDB contains 4511 covalent inhibitors (including 68 approved drugs) with 57 different reactive warheads for 280 protein targets. The crystal structures of some of the proteins bound with a covalent inhibitor are provided to visualize the protein–ligand interactions around the binding site. Each covalent inhibitor is annotated with the structure, warhead, experimental bioactivity, physicochemical properties, etc. Moreover, CovalentInDB provides the covalent reaction mechanism and the corresponding experimental verification methods for each inhibitor towards its target. High-quality datasets are downloadable for users to evaluate and develop computational methods for covalent drug design. CovalentInDB is freely accessible at http://cadd.zju.edu.cn/cidb/.
Wednesday, October 21, 2020
Triple, Mutually Orthogonal Bioorthogonal Pairs through the Design of Electronically Activated Sulfamate-Containing Cycloalkynes
Yun Hu, Jessica M. Roberts, Henry R. Kilgore, Amirah S. Mat Lani, Ronald T. Raines, and Jennifer M. Schomaker
Journal of the American Chemical Society 2020
Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds that are capable of fast and predictable reactions. The ability to easily modify S-, N-, and O-containing cyclooctynes (SNO-OCTs) enables electronic tuning of various SNO-OCTs to influence their cycloaddition rates with Type I–III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant reaction rate enhancements of a difluorinated SNO-OCT derivative, as compared to the parent scaffold, were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 5.13 M–1 s–1. Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.
Thursday, October 15, 2020
Petri, L., Ábrányi-Balogh, P., Imre, T., Pálfy, G., Perczel, A., Knez, D., Hrast, M., Gobec, M., Sosič, I., Nyíri, K., Vértessy, B..G., Jänsch, N., Desczyk, C., Meyer-Almes, F., Ogris, I., Grdadolnik, S..G., Iacovino, L..G., Binda, C., Gobec, S. and Keserű, G..M.
Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by proteomic and computational tools. Here, we present a toolbox of fragments containing a 3,5‐bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing a range of reactivities. We characterized the library members for their reactivity, aqueous stability and specificity for nucleophilic amino acids. By screening this library against a set of enzymes amenable for covalent inhibition, we showed that this approach experimentally characterized the accessibility and reactivity of targeted cysteines. Interesting covalent fragment hits were obtained for all investigated cysteine‐containing enzymes.
Tuesday, October 13, 2020
Bicyclobutane Carboxylic Amide as a Cysteine-Directed Strained Electrophile for Selective Targeting of Proteins
Keisuke Tokunaga, Mami Sato, Keiko Kuwata, Chizuru Miura, Hirokazu Fuchida, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo, Naoya Shindo, and Akio Ojida
Journal of the American Chemical Society 2020
Monday, October 12, 2020
Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma
John M. Hatcher, Guang Yang, Li Wang, Scott B. Ficarro, Sara Buhrlage, Hao Wu, Jarrod A. Marto, Steven P. Treon, and Nathanael S. Gray
ACS Med. Chem. Lett. 2020
Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating the innate immune response against foreign pathogens. Additionally, dysregulation of IRAK1 signaling plays a role in neoplastic disorders. For example, IRAK1 was shown to be important for survival and proliferation in many B-cell lymphomas, including Waldenström’s macroglobulinemia (WM) and ABC subtype Diffused Large B-cell Lymphoma (DLBCL) cells. Here, we report the discovery of a highly potent and selective covalent inhibitor of IRAK1, JH-X-119-01. Intact protein MS labeling studies confirmed that JH-X-119-01 irreversibly labels IRAK1 at C302. This compound exhibited cytotoxic activity at single digit micromolar concentrations in a panel of WM, DLBCL, and lymphoma cell lines expressing MYD88. Cotreatment of JH-X-119-01 with the BTK inhibitor ibrutinib resulted in synergistic killing effects in these systems. Taken together, JH-X-119-01 represents a highly selective probe of IRAK1 for further development.
Sunday, October 11, 2020
Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1)
Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure–activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).
S. Busker1, W. Qian, M. Haraldsson, B. Espinosa, L. Johansson,S. Attarha, I. Kolosenko, J. Liu6, M. Dagnell, D. Grandér, E. S. J. Arnér, K. Pokrovskaja Tamm, and B. D. G. Page
Science Advances 20 Mar 2020:
Vol. 6, no. 12, eaax7945
Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.
Friday, October 9, 2020
Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile
Qichao Bao, Liangying Zhang, Nan Wang, Brian Gabet, Weikang Yang, Xingyang Gao, Qidong You, and Zhengyu Jiang
ACS Medicinal Chemistry Letters 2020
Wednesday, October 7, 2020
Alice Douangamath, Daren Fearon, Paul Gehrtz, Tobias Krojer, Petra Lukacik, C. David Owen, Efrat Resnick, Claire Strain-Damerell, Anthony Aimon, Péter Ábrányi-Balogh, José Brandão-Neto, Anna Carbery, Gemma Davison, Alexandre Dias, Thomas D. Downes, Louise Dunnett, Michael Fairhead, James D. Firth, S. Paul Jones, Aaron Keeley, György M. Keserü, Hanna F. Klein, Mathew P. Martin, Martin E. M. Noble, Peter O’Brien, Ailsa Powell, Rambabu N. Reddi, Rachael Skyner, Matthew Snee, Michael J. Waring, Conor Wild, Nir London, Frank von Delft & Martin A. Walsh -
Nat Commun 11, 5047 (2020).
COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.
Tuesday, October 6, 2020
Thomas A. Baillie (2020) Approaches to Mitigate the Risk of Serious Adverse Reactions in Covalent Drug Design, Expert Opinion on Drug Discovery
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...
Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable ProteomeKatharine Gilbert, Aini Vuorinen, Arron Aatkar Peter Pogány, Jonathan Pettinger, Joanna M. Kirkpatrick, Katrin Rittinger∥, David House, Glen...
Discovery of Non-Cysteine-Targeting Covalent Inhibitors by Activity-Based Proteomic Screening with a Cysteine-Reactive ProbeYejin Jung, Naotaka Noda, Junichiro Takaya, Masahiro Abo, Kohei Toh, Ken Tajiri, Changyi Cui, Lu Zhou, Shin-ichi Sato, and Motonari Uesugi A...
Madeline E Kavanagh, Benjamin D Horning, Roli Khattri, Nilotpal Roy, Justine P Lu, Landon R Whitby, Jaclyn C Brannon, Albert Parker, Joel M ...