abstract：:Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle th...

journal_title：Journal of medicinal chemistry

authors： Chen L,Zhuang C,Lu J,Jiang Y,Sheng C

更新日期：2018-03-22 00:00:00

abstract：:Multidrug-resistant Staphylococcus aureus, including MRSA (methicillin-resistant) and VRSA (vancomycin-resistant), causes serious healthcare-associated infections, even sepsis and death. Here, we identified six novel cathelicidins (CATHPb1-6) from Python bivittatu, and CATHPb1 displayed the best in vitro pharmacologic...

journal_title：Journal of medicinal chemistry

authors： Cai S,Qiao X,Feng L,Shi N,Wang H,Yang H,Guo Z,Wang M,Chen Y,Wang Y,Yu H

更新日期：2018-03-08 00:00:00

abstract：:A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in v...

journal_title：Journal of medicinal chemistry

authors： Adams CM,Anderson K,Artman G 3rd,Bizec JC,Cepeda R,Elliott J,Fassbender E,Ghosh M,Hanks S,Hardegger LA,Hosagrahara VP,Jaffee B,Jendza K,Ji N,Johnson L,Lee W,Liu D,Liu F,Long D,Ma F,Mainolfi N,Meredith EL,Miran

更新日期：2018-02-22 00:00:00

abstract：:The combination of early diagnosis and complete surgical resection offers the greatest prospect of curative cancer treatment. An iodine-124/fluorescein-based dual-modality labeling reagent, 124I-Green, constitutes a generic tool for one-step installation of a positron emission tomography (PET) and a fluorescent report...

journal_title：Journal of medicinal chemistry

authors： Lu Z,Pham TT,Rajkumar V,Yu Z,Pedley RB,Årstad E,Maher J,Yan R

更新日期：2018-02-22 00:00:00

abstract：:We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compou...

journal_title：Journal of medicinal chemistry

authors： Banerjee S,Arnst KE,Wang Y,Kumar G,Deng S,Yang L,Li GB,Yang J,White SW,Li W,Miller DD

更新日期：2018-02-22 00:00:00

abstract：:The plant metabolite 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME, compound 6) was synthesized, and its potential effect on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby canine kidney cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule (MT) mod...

journal_title：Journal of medicinal chemistry

authors： Abd El-Salam M,Bastos JK,Han JJ,Previdi D,Coelho EB,Donate PM,Romero MF,Lieske J

更新日期：2018-02-22 00:00:00

abstract：:Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first 18F-labeled optimized lead suitable for in vivo imaging of Trk, [18F]TRACK, which is radiosynthesized with ease from a n...

journal_title：Journal of medicinal chemistry

authors： Bernard-Gauthier V,Mossine AV,Mahringer A,Aliaga A,Bailey JJ,Shao X,Stauff J,Arteaga J,Sherman P,Grand'Maison M,Rochon PL,Wängler B,Wängler C,Bartenstein P,Kostikov A,Kaplan DR,Fricker G,Rosa-Neto P,Scott PJH,Schirr

更新日期：2018-02-22 00:00:00

abstract：:A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical f...

journal_title：Journal of medicinal chemistry

authors： Wang Y,Zhi Y,Jin Q,Lu S,Lin G,Yuan H,Yang T,Wang Z,Yao C,Ling J,Guo H,Li T,Jin J,Li B,Zhang L,Chen Y,Lu T

更新日期：2018-02-22 00:00:00

abstract：:Pan assay interference compounds (PAINS) have become a paradigm for compound classes that might cause artifacts in biological assays. PAINS-defining substructures are typically contained in larger compounds. We have systematically examined X-ray structures of protein-ligand complexes for compounds containing PAINS mot...

journal_title：Journal of medicinal chemistry

authors： Gilberg E,Gütschow M,Bajorath J

更新日期：2018-02-08 00:00:00

abstract：:The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of ...

journal_title：Journal of medicinal chemistry

authors： Wu CH,Song JS,Kuan HH,Wu SH,Chou MC,Jan JJ,Tsou LK,Ke YY,Chen CT,Yeh KC,Wang SY,Yeh TK,Tseng CT,Huang CL,Wu MH,Kuo PC,Lee CJ,Shia KS

更新日期：2018-02-08 00:00:00

abstract：:NAD+ has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD+ on mitochondrial fitness, metabolism, and li...

journal_title：Journal of medicinal chemistry

authors： Pellicciari R,Liscio P,Giacchè N,De Franco F,Carotti A,Robertson J,Cialabrini L,Katsyuba E,Raffaelli N,Auwerx J

更新日期：2018-02-08 00:00:00

abstract：:(E)-Vinylphosphonate ((E)-VP), a metabolically stable phosphate mimic at the 5'-end of the antisense strand, enhances the in vivo potency of siRNA. Here we describe a straightforward synthetic approach to incorporate a nucleotide carrying a vinylphosphonate (VP) moiety at the 5'-end of oligonucleotides under standard ...

journal_title：Journal of medicinal chemistry

authors： Parmar RG,Brown CR,Matsuda S,Willoughby JLS,Theile CS,Charissé K,Foster DJ,Zlatev I,Jadhav V,Maier MA,Egli M,Manoharan M,Rajeev KG

更新日期：2018-02-08 00:00:00

abstract：:This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase i...

journal_title：Journal of medicinal chemistry

authors： Mazur M,Olczak J,Olejniczak S,Koralewski R,Czestkowski W,Jedrzejczak A,Golab J,Dzwonek K,Dymek B,Sklepkiewicz PL,Zagozdzon A,Noonan T,Mahboubi K,Conway B,Sheeler R,Beckett P,Hungerford WM,Podjarny A,Mitschler A,Cous

更新日期：2018-02-08 00:00:00

abstract：:Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional aff...

journal_title：Journal of medicinal chemistry

authors： Peterson K,Kumar R,Stenström O,Verma P,Verma PR,Håkansson M,Kahl-Knutsson B,Zetterberg F,Leffler H,Akke M,Logan DT,Nilsson UJ

更新日期：2018-02-08 00:00:00

abstract：:Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR rever...

journal_title：Journal of medicinal chemistry

authors： Huff SE,Mohammed FA,Yang M,Agrawal P,Pink J,Harris ME,Dealwis CG,Viswanathan R

更新日期：2018-02-08 00:00:00

abstract：:Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as report...

journal_title：Journal of medicinal chemistry

authors： Ren J,Zhao Y,Fry EE,Stuart DI

更新日期：2018-02-08 00:00:00

abstract：:PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive struct...

journal_title：Journal of medicinal chemistry

authors： Kaniskan HÜ,Eram MS,Zhao K,Szewczyk MM,Yang X,Schmidt K,Luo X,Xiao S,Dai M,He F,Zang I,Lin Y,Li F,Dobrovetsky E,Smil D,Min SJ,Lin-Jones J,Schapira M,Atadja P,Li E,Barsyte-Lovejoy D,Arrowsmith CH,Brown PJ,Liu

更新日期：2018-02-08 00:00:00

abstract：:The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labeling has shifted toward the use of allosteric mechanisms over classical activity-based approaches. Allosteric enzyme regul...

journal_title：Journal of medicinal chemistry

authors： Paiva SL,da Silva SR,de Araujo ED,Gunning PT

更新日期：2018-01-25 00:00:00

abstract：:The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis a...

journal_title：Journal of medicinal chemistry

authors： Matyskiela ME,Zhang W,Man HW,Muller G,Khambatta G,Baculi F,Hickman M,LeBrun L,Pagarigan B,Carmel G,Lu CC,Lu G,Riley M,Satoh Y,Schafer P,Daniel TO,Carmichael J,Cathers BE,Chamberlain PP

更新日期：2018-01-25 00:00:00

abstract：:CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus ...

journal_title：Journal of medicinal chemistry

authors： Li B,Ni S,Mao F,Chen F,Liu Y,Wei H,Chen W,Zhu J,Lan L,Li J

更新日期：2018-01-11 00:00:00

abstract：:A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compoun...

journal_title：Journal of medicinal chemistry

authors： Chrovian CC,Soyode-Johnson A,Peterson AA,Gelin CF,Deng X,Dvorak CA,Carruthers NI,Lord B,Fraser I,Aluisio L,Coe KJ,Scott B,Koudriakova T,Schoetens F,Sepassi K,Gallacher DJ,Bhattacharya A,Letavic MA

更新日期：2018-01-11 00:00:00

abstract：:The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a v...

journal_title：Journal of medicinal chemistry

authors： Bronner SM,Murray J,Romero FA,Lai KW,Tsui V,Cyr P,Beresini MH,de Leon Boenig G,Chen Z,Choo EF,Clark KR,Crawford TD,Jayaram H,Kaufman S,Li R,Li Y,Liao J,Liang X,Liu W,Ly J,Maher J,Wai J,Wang F,Zheng A,Zhu X

更新日期：2017-12-28 00:00:00

abstract：:New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangos...

journal_title：Journal of medicinal chemistry

authors： Lin S,Sin WLW,Koh JJ,Lim F,Wang L,Cao D,Beuerman RW,Ren L,Liu S

更新日期：2017-12-28 00:00:00

abstract：:Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of t...

journal_title：Journal of medicinal chemistry

authors： Ouyang L,Zhang L,Liu J,Fu L,Yao D,Zhao Y,Zhang S,Wang G,He G,Liu B

更新日期：2017-12-28 00:00:00

abstract：:Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a maste...

journal_title：Journal of medicinal chemistry

authors： Choi H,Ham SY,Cha E,Shin Y,Kim HS,Bang JK,Son SH,Park HD,Byun Y

更新日期：2017-12-14 00:00:00

abstract：:Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7)...

journal_title：Journal of medicinal chemistry

authors： Gregson SJ,Masterson LA,Wei B,Pillow TH,Spencer SD,Kang GD,Yu SF,Raab H,Lau J,Li G,Lewis Phillips GD,Gunzner-Toste J,Safina BS,Ohri R,Darwish M,Kozak KR,Dela Cruz-Chuh J,Polson A,Flygare JA,Howard PW

更新日期：2017-12-14 00:00:00

abstract：:Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective ...

journal_title：Journal of medicinal chemistry

authors： Romero FA,Murray J,Lai KW,Tsui V,Albrecht BK,An L,Beresini MH,de Leon Boenig G,Bronner SM,Chan EW,Chen KX,Chen Z,Choo EF,Clagg K,Clark K,Crawford TD,Cyr P,de Almeida Nagata D,Gascoigne KE,Grogan JL,Hatzivassiliou

更新日期：2017-11-22 00:00:00

abstract：:Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology...

journal_title：Journal of medicinal chemistry

authors： Geist L,Mayer M,Cockcroft XL,Wolkerstorfer B,Kessler D,Engelhardt H,McConnell DB,Konrat R

更新日期：2017-11-09 00:00:00

abstract：:Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of...

journal_title：Journal of medicinal chemistry

authors： Shao LD,Su J,Ye B,Liu JX,Zuo ZL,Li Y,Wang YY,Xia C,Zhao QS

更新日期：2017-11-09 00:00:00

abstract：:A unique, dual-function, photoactivatable anticancer prodrug, RuEuL, has been tailored that features a ruthenium(II) complex linked to a cyclen-europium chelate via a π-conjugated bridge. Under irradiation at 488 nm, the dark-inactive prodrug undergoes photodissociation, releasing the DNA-damaging ruthenium species. U...

journal_title：Journal of medicinal chemistry

authors： Li H,Xie C,Lan R,Zha S,Chan CF,Wong WY,Ho KL,Chan BD,Luo Y,Zhang JX,Law GL,Tai WCS,Bünzli JG,Wong KL

更新日期：2017-11-09 00:00:00

abstract：:There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activat...

journal_title：Journal of medicinal chemistry

authors： Schillaci D,Spanò V,Parrino B,Carbone A,Montalbano A,Barraja P,Diana P,Cirrincione G,Cascioferro S

更新日期：2017-10-26 00:00:00

abstract：:The use of privileged structures in drug discovery has proven to be an effective strategy, allowing the generation of innovative hits/leads and successful optimization processes. Chromone is recognized as a privileged structure and a useful template for the design of novel compounds with potential pharmacological inte...

journal_title：Journal of medicinal chemistry

authors： Reis J,Gaspar A,Milhazes N,Borges F

更新日期：2017-10-12 00:00:00

abstract：:The quinazoline class was exploited to search for a new translocator protein (TSPO) fluorescent probe endowed with improved affinity and residence time (RT). Computational studies on an "in-house" collection of quinazoline derivatives, featuring highly steric demanding groups at the amide nitrogen, suggested that, des...

journal_title：Journal of medicinal chemistry

authors： Milite C,Barresi E,Da Pozzo E,Costa B,Viviano M,Porta A,Messere A,Sbardella G,Da Settimo F,Novellino E,Cosconati S,Castellano S,Taliani S,Martini C

更新日期：2017-09-28 00:00:00

abstract：:Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs diffe...

journal_title：Journal of medicinal chemistry

authors： Zhu JY,Cuellar RA,Berndt N,Lee HE,Olesen SH,Martin MP,Jensen JT,Georg GI,Schönbrunn E

更新日期：2017-09-28 00:00:00

abstract：:The dopamine D4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D4, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D4 antag...

journal_title：Journal of medicinal chemistry

authors： Lindsley CW,Hopkins CR

更新日期：2017-09-14 00:00:00

abstract：:The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the...

journal_title：Journal of medicinal chemistry

authors： Chrysanthopoulos PK,Mujumdar P,Woods LA,Dolezal O,Ren B,Peat TS,Poulsen SA

更新日期：2017-09-14 00:00:00

abstract：:The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on e...

journal_title：Journal of medicinal chemistry

authors： Bernard-Gauthier V,Bailey JJ,Mossine AV,Lindner S,Vomacka L,Aliaga A,Shao X,Quesada CA,Sherman P,Mahringer A,Kostikov A,Grand'Maison M,Rosa-Neto P,Soucy JP,Thiel A,Kaplan DR,Fricker G,Wängler B,Bartenstein P,Schirrm

更新日期：2017-08-24 00:00:00

abstract：:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all ...

journal_title：Journal of medicinal chemistry

authors： Okawa T,Aramaki Y,Yamamoto M,Kobayashi T,Fukumoto S,Toyoda Y,Henta T,Hata A,Ikeda S,Kaneko M,Hoffman ID,Sang BC,Zou H,Kawamoto T

更新日期：2017-08-24 00:00:00

abstract：:The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different se...

journal_title：Journal of medicinal chemistry

authors： Yamada K,Levell J,Yoon T,Kohls D,Yowe D,Rigel DF,Imase H,Yuan J,Yasoshima K,DiPetrillo K,Monovich L,Xu L,Zhu M,Kato M,Jain M,Idamakanti N,Taslimi P,Kawanami T,Argikar UA,Kunjathoor V,Xie X,Yagi YI,Iwaki Y,Ro

更新日期：2017-08-24 00:00:00

abstract：:The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great ...

journal_title：Journal of medicinal chemistry

authors： Soubhye J,Chikh Alard I,Aldib I,Prévost M,Gelbcke M,De Carvalho A,Furtmüller PG,Obinger C,Flemmig J,Tadrent S,Meyer F,Rousseau A,Nève J,Mathieu V,Zouaoui Boudjeltia K,Dufrasne F,Van Antwerpen P

更新日期：2017-08-10 00:00:00