abstract：:Necrosis is the main mode of cell death, which leads to multiple clinical conditions affecting hundreds of millions of people worldwide. Its molecular mechanisms are poorly understood, hampering therapeutics development. Here, we identify key proteolytic activities essential for necrosis using various biochemical appr...

journal_title：Journal of medicinal chemistry

authors： Khalfin B,Lichtenstein A,Albeck A,Nathan I

更新日期：2021-01-31 00:00:00

abstract：:GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as a...

journal_title：Journal of medicinal chemistry

authors： Wang C,Zhang YF,Guo S,Zhao Q,Zeng Y,Xie Z,Xie X,Lu B,Hu Y

更新日期：2021-01-28 00:00:00

abstract：:Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppre...

journal_title：Journal of medicinal chemistry

authors： Lin H,Sharabi K,Lin L,Ruiz C,Zhu D,Cameron MD,Novick SJ,Griffin PR,Puigserver P,Kamenecka TM

更新日期：2021-01-28 00:00:00

abstract：:Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to...

journal_title：Journal of medicinal chemistry

authors： Begnini F,Poongavanam V,Over B,Castaldo M,Geschwindner S,Johansson P,Tyagi M,Tyrchan C,Wissler L,Sjö P,Schiesser S,Kihlberg J

更新日期：2021-01-28 00:00:00

abstract：:A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progresse...

journal_title：Journal of medicinal chemistry

authors： Preston S,Garcia-Bustos J,Hall LG,Martin SD,Le TG,Kundu A,Ghoshal A,Nguyen NH,Jiao Y,Ruan B,Xue L,Huang F,Chang BCH,McGee SL,Wells TNC,Palmer MJ,Jabbar A,Gasser RB,Baell JB

更新日期：2021-01-14 00:00:00

abstract：:We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate exp...

journal_title：Journal of medicinal chemistry

authors： Majellaro M,Jespers W,Crespo A,Núñez MJ,Novio S,Azuaje J,Prieto-Díaz R,Gioé C,Alispahic B,Brea J,Loza MI,Freire-Garabal M,Garcia-Santiago C,Rodríguez-García C,García-Mera X,Caamaño O,Fernandez-Masaguer C,Sardina JF,St

更新日期：2021-01-14 00:00:00

abstract：:Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and oth...

journal_title：Journal of medicinal chemistry

authors： Dietrich JD,Longenecker KL,Wilson NS,Goess C,Panchal SC,Swann SL,Petros AM,Hobson AD,Ihle D,Song D,Richardson P,Comess KM,Cox PB,Dombrowski A,Sarris K,Donnelly-Roberts DL,Duignan DB,Gomtsyan A,Jung P,Krueger AC,Ma

更新日期：2021-01-14 00:00:00

abstract：:Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to o...

journal_title：Journal of medicinal chemistry

authors： Hiesinger K,Dar'in D,Proschak E,Krasavin M

更新日期：2021-01-14 00:00:00

abstract：:Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and poten...

journal_title：Journal of medicinal chemistry

authors： Thorat SA,Lee Y,Jung A,Ann J,Ahn S,Baek J,Zuo D,Do N,Jeong JJ,Blumberg PM,Esch TE,Turcios NA,Pearce LV,Ha HJ,Yoo YD,Hong S,Choi S,Lee J

更新日期：2021-01-14 00:00:00

abstract：:Although the majority of proteins used for biomedical research are produced using living systems such as bacteria, biological means for producing proteins can be advantageously complemented by protein semisynthesis or total chemical synthesis. The latter approach is particularly useful when the proteins to be produced...

journal_title：Journal of medicinal chemistry

authors： Agouridas V,El Mahdi O,Melnyk O

更新日期：2020-12-24 00:00:00

abstract：:In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized....

journal_title：Journal of medicinal chemistry

authors： Zhang M,Xu B,Li N,Liu H,Shi X,Zhang Q,Shi Y,Xu K,Xiao J,Chen D,Zhu H,Sun Y,Zhang T,Zhang R,Fang Q

更新日期：2020-12-24 00:00:00

abstract：:Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attr...

journal_title：Journal of medicinal chemistry

authors： Kounde CS,Tate EW

更新日期：2020-12-24 00:00:00

abstract：:Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their des...

journal_title：Journal of medicinal chemistry

authors： Heidtmann CV,Voukia F,Hansen LN,Sørensen SH,Urlund B,Nielsen S,Pedersen M,Kelawi N,Andersen BN,Pedersen M,Reinholdt P,Kongsted J,Nielsen CU,Klitgaard JK,Nielsen P

更新日期：2020-12-24 00:00:00

abstract：:Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CG...

journal_title：Journal of medicinal chemistry

authors： Gona K,Toczek J,Ye Y,Sanzida N,Golbazi A,Boodagh P,Salarian M,Jung JJ,Rajendran S,Kukreja G,Wu TL,Devel L,Sadeghi MM

更新日期：2020-12-10 00:00:00

abstract：:In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the...

journal_title：Journal of medicinal chemistry

authors： Yang T,Hu M,Chen Y,Xiang M,Tang M,Qi W,Shi M,He J,Yuan X,Zhang C,Liu K,Li J,Yang Z,Chen L

更新日期：2020-12-10 00:00:00

abstract：:Focal adhesion kinase (FAK) is a nonreceptor intracellular tyrosine kinase that plays an essential role in cancer cell adhesion, survival, proliferation, and migration through both its enzymatic activities and scaffolding functions. Overexpression of FAK has been found in many human cancer cells from different origins...

journal_title：Journal of medicinal chemistry

authors： Lu Y,Sun H

更新日期：2020-12-10 00:00:00

abstract：:We report compounds 5 (CG416) and 6 (CG428) as two first-in-class tropomyosin receptor kinase (TRK) degraders that target the intracellular kinase domain of TRK. Degraders 5 and 6 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling ...

journal_title：Journal of medicinal chemistry

authors： Chen L,Chen Y,Zhang C,Jiao B,Liang S,Tan Q,Chai H,Yu W,Qian Y,Yang H,Yao W,Yu J,Luo Y,Plewe M,Wang J,Han XR,Liu J

更新日期：2020-12-10 00:00:00

abstract：:A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of...

journal_title：Journal of medicinal chemistry

authors： Guo J,Luo L,Wang Z,Hu N,Wang W,Xie F,Liang E,Yan X,Xiao J,Li S

更新日期：2020-11-25 00:00:00

abstract：:As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cyto...

journal_title：Journal of medicinal chemistry

authors： Alverez CN,Park JE,Toti KS,Xia Y,Krausz KW,Rai G,Bang JK,Gonzalez FJ,Jacobson KA,Lee KS

更新日期：2020-11-25 00:00:00

abstract：:The enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) catalyzes the final step in the biosynthesis of epinephrine and is a potential drug target, primarily for the control of hypertension. Unfortunately, many potent PNMT inhibitors also possess significant affinity for the a2-adrenoceptor, which compli...

journal_title：Journal of medicinal chemistry

authors： Lu J,Bart AG,Wu Q,Criscione KR,McLeish MJ,Scott EE,Grunewald GL

更新日期：2020-11-25 00:00:00

abstract：:Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction networ...

journal_title：Journal of medicinal chemistry

authors： Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z

更新日期：2020-11-25 00:00:00

abstract：:The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sit...

journal_title：Journal of medicinal chemistry

authors： Hoffman RL,Kania RS,Brothers MA,Davies JF,Ferre RA,Gajiwala KS,He M,Hogan RJ,Kozminski K,Li LY,Lockner JW,Lou J,Marra MT,Mitchell LJ Jr,Murray BW,Nieman JA,Noell S,Planken SP,Rowe T,Ryan K,Smith GJ 3rd,Solowiej

更新日期：2020-11-12 00:00:00

abstract：:The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acq...

journal_title：Journal of medicinal chemistry

authors： Kumari S,Carmona AV,Tiwari AK,Trippier PC

更新日期：2020-11-12 00:00:00

abstract：:Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI ri...

journal_title：Journal of medicinal chemistry

authors： Norman BH

更新日期：2020-10-22 00:00:00

abstract：:Macrophage migration inhibitory factor (MIF) is a cytokine with key roles in inflammation and cancer, which qualifies it as a potential drug target. Apart from its cytokine activity, MIF also harbors enzyme activity for keto-enol tautomerization. MIF enzymatic activity has been used for identification of MIF binding m...

journal_title：Journal of medicinal chemistry

authors： Xiao Z,Chen D,Song S,van der Vlag R,van der Wouden PE,van Merkerk R,Cool RH,Hirsch AKH,Melgert BN,Quax WJ,Poelarends GJ,Dekker FJ

更新日期：2020-10-22 00:00:00

abstract：:Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expr...

journal_title：Journal of medicinal chemistry

authors： Beck H,Thaler T,Meibom D,Meininghaus M,Jörißen H,Dietz L,Terjung C,Bairlein M,von Bühler CJ,Anlauf S,Fürstner C,Stellfeld T,Schneider D,Gericke KM,Buyck T,Lovis K,Münster U,Anlahr J,Kersten E,Levilain G,Marossek V

更新日期：2020-10-22 00:00:00

abstract：:The thioredoxin system plays an important role in cancer cells. Inhibiting thioredoxin reductase (TrxR) has emerged as an effective strategy to selectively target cancer cells. Withangulatin A (WA), a natural product extracted from the whole herb of Physalis angulata L. (Solanaceae), exhibits potent anticancer activit...

journal_title：Journal of medicinal chemistry

authors： Wang C,Li S,Zhao J,Yang H,Yin F,Ding M,Luo J,Wang X,Kong L

更新日期：2020-10-08 00:00:00

abstract：:The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target o...

journal_title：Journal of medicinal chemistry

authors： Zhou HS,Hu LB,Zhang H,Shan WX,Wang Y,Li X,Liu T,Zhao J,You QD,Jiang ZY

更新日期：2020-10-08 00:00:00

abstract：:The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of poten...

journal_title：Journal of medicinal chemistry

authors： Drew SL,Thomas-Tran R,Beatty JW,Fournier J,Lawson KV,Miles DH,Mata G,Sharif EU,Yan X,Mailyan AK,Ginn E,Chen J,Wong K,Soni D,Dhanota P,Chen PY,Shaqfeh SG,Meleza C,Pham AT,Chen A,Zhao X,Banuelos J,Jin L,Schind

更新日期：2020-10-08 00:00:00

abstract：:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...

journal_title：Journal of medicinal chemistry

authors： Reßing N,Sönnichsen M,Osko JD,Schöler A,Schliehe-Diecks J,Skerhut A,Borkhardt A,Hauer J,Kassack MU,Christianson DW,Bhatia S,Hansen FK

更新日期：2020-09-24 00:00:00

abstract：:Photodynamic therapy (PDT) as a rising platform of the cancer treatment method is receiving increased attention. Through systematic evaluation of halogen substitution on aza-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPY), we have found that monoiodo-derived aza-BODIPYs provided greater efficacy than other haloge...

journal_title：Journal of medicinal chemistry

authors： Yu Z,Zhou J,Ji X,Lin G,Xu S,Dong X,Zhao W

更新日期：2020-09-10 00:00:00

abstract：:Vitamin D receptor (VDR) antagonists prevent the VDR activation function helix 12 from folding into its active conformation, thus affecting coactivator recruitment and antagonizing the transcriptional regulation induced by 1α,25-dihydroxyvitamin D3. Here, we report the crystal structure of the zebrafish VDR ligand-bin...

journal_title：Journal of medicinal chemistry

authors： Belorusova AY,Chalhoub S,Rovito D,Rochel N

更新日期：2020-09-10 00:00:00

abstract：:The 3,4-dichloro-N-(1-(dimethylamino)cyclohexyl)methyl benzamide scaffold was studied as a template for 18F-positron emission tomography (18F-PET) radiotracer development emphasizing sensitivity to changes in opioid receptor (OR) occupancy over high affinity. Agonist potency, binding affinity, and relevant pharmacolog...

journal_title：Journal of medicinal chemistry

authors： Ott J,Spilhaug MM,Maschauer S,Rafique W,Jakobsson JE,Hartvig K,Hübner H,Gmeiner P,Prante O,Riss PJ

更新日期：2020-09-10 00:00:00

abstract：:Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high ...

journal_title：Journal of medicinal chemistry

authors： Czako B,Marszalek JR,Burke JP,Mandal P,Leonard PG,Cross JB,Mseeh F,Jiang Y,Chang EQ,Suzuki E,Kovacs JJ,Feng N,Gera S,Harris AL,Liu Z,Mullinax RA,Pang J,Parker CA,Spencer ND,Yu SS,Wu Q,Tremblay MR,Mikule K,Wi

更新日期：2020-09-10 00:00:00

abstract：:The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we descri...

journal_title：Journal of medicinal chemistry

authors： Mahindra A,Janha O,Mapesa K,Sanchez-Azqueta A,Alam MM,Amambua-Ngwa A,Nwakanma DC,Tobin AB,Jamieson AG

更新日期：2020-09-10 00:00:00

abstract：:Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-base...

journal_title：Journal of medicinal chemistry

authors： Bonnel C,Legrand B,Simon M,Clavié M,Masnou A,Jumas-Bilak E,Kang YK,Licznar-Fajardo P,Maillard LT,Masurier N

更新日期：2020-09-10 00:00:00

abstract：:Network theory provides one of the most potent analysis tools for the study of complex systems. In this paper, we illustrate the network-based perspective in drug research and how it is coherent with the new paradigm of drug discovery. We first present data sources from which networks are built, then show some example...

journal_title：Journal of medicinal chemistry

authors： Recanatini M,Cabrelle C

更新日期：2020-08-27 00:00:00

abstract：:The kinome-wide virtual profiling of small molecules with high-dimensional structure-activity data is a challenging task in drug discovery. Here, we present a virtual profiling model against a panel of 391 kinases based on large-scale bioactivity data and the multitask deep neural network algorithm. The obtained model...

journal_title：Journal of medicinal chemistry

authors： Li X,Li Z,Wu X,Xiong Z,Yang T,Fu Z,Liu X,Tan X,Zhong F,Wan X,Wang D,Ding X,Yang R,Hou H,Li C,Liu H,Chen K,Jiang H,Zheng M

更新日期：2020-08-27 00:00:00

abstract：:The receptor CRM1 is responsible for the nuclear export of many tumor-suppressor proteins and viral ribonucleoproteins. This renders CRM1 an interesting target for therapeutic intervention in diverse cancer types and viral diseases. Structural studies of Saccharomyces cerevisiae CRM1 ( Sc ...

journal_title：Journal of medicinal chemistry

authors： Shaikhqasem A,Dickmanns A,Neumann P,Ficner R

更新日期：2020-07-23 00:00:00

abstract：:The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amph...

journal_title：Journal of medicinal chemistry

authors： Kollar J,Machacek M,Halaskova M,Lenco J,Kucera R,Demuth J,Rohlickova M,Hasonova K,Miletin M,Novakova V,Zimcik P

更新日期：2020-07-23 00:00:00