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3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders J. Med. Chem. (IF 7.446) Pub Date : 2022-06-24 Radek Jorda, Libor Havlíček, Miroslav Peřina, Veronika Vojáčková, Tomáš Pospíšil, Stefan Djukic, Jana Škerlová, Jiří Grúz, Nicol Renešová, Pavel Klener, Pavlína Řezáčová, Miroslav Strnad, Vladimír Kryštof
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Novel Hydroxychalcone-Based Dual Inhibitors of Aldose Reductase and α-Glucosidase as Potential Therapeutic Agents against Diabetes Mellitus and Its Complications J. Med. Chem. (IF 7.446) Pub Date : 2022-06-24 Xiaonan Zhang, Long Xu, Huan Chen, Xin Zhang, Yanqi Lei, Wenchao Liu, Hulin Xu, Bing Ma, Changjin Zhu
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Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors J. Med. Chem. (IF 7.446) Pub Date : 2022-06-23 Osvaldo Burastero, Lucas A. Defelipe, Gabriel Gola, Nancy L. Tateosian, Elias D. Lopez, Camila Belen Martinena, Juan Pablo Arcon, Martín Dodes Traian, Diana E. Wetzler, Isabel Bento, Xavier Barril, Javier Ramirez, Marcelo A. Marti, Maria M. Garcia-Alai, Adrián G. Turjanski
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Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents with Collateral Sensitivity against MCF-7/ADR J. Med. Chem. (IF 7.446) Pub Date : 2022-06-23 Zhihui Yu, Mengru Li, Ke Wang, Yuting Gu, Shiqi Guo, Weijie Wang, Yulei Ma, Hongrui Liu, Ying Chen
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Evolutionary and Structural Insights about Potential SARS-CoV-2 Evasion of Nirmatrelvir J. Med. Chem. (IF 7.446) Pub Date : 2022-06-22 Kai S. Yang, Sunshine Z. Leeuwon, Shiqing Xu, Wenshe Ray Liu
The U.S. FDA approval of PAXLOVID, a combination therapy of nirmatrelvir and ritonavir has significantly boosted our morale in fighting the COVID-19 pandemic. Nirmatrelvir is an inhibitor of the main protease (MPro) of SARS-CoV-2. Since many SARS-CoV-2 variants that resist vaccines and antibodies have emerged, a concern of acquired viral resistance to nirmatrelvir naturally arises. Here, possible mutations
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Rings in Clinical Trials and Drugs: Present and Future J. Med. Chem. (IF 7.446) Pub Date : 2022-06-22 Jonathan Shearer, Jose L. Castro, Alastair D. G. Lawson, Malcolm MacCoss, Richard D. Taylor
We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for newly approved drugs. We also show there are approximately 450 000 unique ring systems derived from 2.24
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Examining the Role of the Linker in Bitopic N6-Substituted Adenosine Derivatives Acting as Biased Adenosine A1 Receptor Agonists J. Med. Chem. (IF 7.446) Pub Date : 2022-06-21 Jon Kyle Awalt, Anh T.N. Nguyen, Tim J. Fyfe, Bui San Thai, Paul J. White, Arthur Christopoulos, Manuela Jörg, Lauren T. May, Peter J. Scammells
The adenosine A1 receptor is a therapeutic target based on its ability to provide cardioprotection during episodes of myocardial ischemia and reperfusion injury. However, the clinical translation of A1R agonists has been hindered by dose-limiting adverse effects (bradycardia and hypotension). Previously, we demonstrated that the bitopic agonist VCP746 (1), consisting of an adenosine pharmacophore linked
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Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4 J. Med. Chem. (IF 7.446) Pub Date : 2022-06-21 E. Scott Priestley, Jacques Banville, Daniel Deon, Laurence Dubé, Marc Gagnon, Julia Guy, Philippe Lapointe, Jean-François Lavallée, Alain Martel, Serge Plamondon, Roger Rémillard, Edward Ruediger, François Tremblay, Shana L. Posy, Victor R. Guarino, Jeremy M. Richter, Jianqing Li, Anuradha Gupta, Muthalagu Vetrichelvan, T. J. Balapragalathan, Arvind Mathur, Ji Hua, Mario Callejo, Jocelyne Guay, Chi
Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class
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Rational Design of a Theranostic Agent Triggered by Endogenous Nitric Oxide in a Cellular Model of Alzheimer’s Disease J. Med. Chem. (IF 7.446) Pub Date : 2022-06-21 Kang Lu, Yu Wang, Hao Zhang, Cuiqing Tian, Wenxiang Wang, Tian Yang, Baiwen Qi, Song Wu
Oxidative damage caused by upregulated nitric oxide (NO) plays an important role in the pathogenesis of Alzheimer’s disease (AD). Currently, stimulus-triggered theranostic agents have received much attention due to benefits on disease imaging and targeted therapeutic effects. However, the development of a theranostic agent triggered by NO for AD remains unexplored. Herein, through the mechanism analysis
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Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors J. Med. Chem. (IF 7.446) Pub Date : 2022-06-21 Hao Zhang, John Ginn, Wenhu Zhan, Yi J. Liu, Annie Leung, Akinori Toita, Rei Okamoto, Tzu-Tshin Wong, Toshihiro Imaeda, Ryoma Hara, Takafumi Yukawa, Mayako Michino, Jeremie Vendome, Thijs Beuming, Kenjiro Sato, Kazuyoshi Aso, Peter T. Meinke, Carl F. Nathan, Laura A. Kirkman, Gang Lin
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Discovery of Novel Benzo[4,5]imidazo[1,2-a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists J. Med. Chem. (IF 7.446) Pub Date : 2022-06-17 Shuhao Liu, Wen Ding, Weifeng Huang, Zhijing Zhang, Yinfeng Guo, Qiyi Zhang, Linna Wu, Yukai Li, Rui Qin, Jiahao Li, Taoda Shi, Xiaolei Zhang, Jinping Lei, Wenhao Hu
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RELATION: A Deep Generative Model for Structure-Based De Novo Drug Design J. Med. Chem. (IF 7.446) Pub Date : 2022-06-17 Mingyang Wang, Chang-Yu Hsieh, Jike Wang, Dong Wang, Gaoqi Weng, Chao Shen, Xiaojun Yao, Zhitong Bing, Honglin Li, Dongsheng Cao, Tingjun Hou
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Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters J. Med. Chem. (IF 7.446) Pub Date : 2022-06-16 Alexander F. Kiefer, Spyridon Bousis, Mostafa M. Hamed, Eleonora Diamanti, Jörg Haupenthal, Anna K.H. Hirsch
Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target that is not addressed by any antibiotic in the market. Since the ECF module is crucial for the vitamin transport mechanism, the prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell
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Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs) J. Med. Chem. (IF 7.446) Pub Date : 2022-06-16 Xue Yuan, Yong Chen, Minghai Tang, Yuhan Wei, Mingsong Shi, Yingxue Yang, Yanting Zhou, Tao Yang, Jiang Liu, Kongjun Liu, Dexin Deng, Chufeng Zhang, Lijuan Chen
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Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination J. Med. Chem. (IF 7.446) Pub Date : 2022-06-16 Thanigaimalai Pillaiyar, Philipp Flury, Nadine Krüger, Haixia Su, Laura Schäkel, Elany Barbosa Da Silva, Olga Eppler, Thales Kronenberger, Tianqing Nie, Stephanie Luedtke, Cheila Rocha, Katharina Sylvester, Marvin R.I. Petry, James H. McKerrow, Antti Poso, Stefan Pöhlmann, Michael Gütschow, Anthony J. O’Donoghue, Yechun Xu, Christa E. Müller, Stefan A. Laufer
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Accelerated Identification of Cell Active KRAS Inhibitory Macrocyclic Peptides using Mixture Libraries and Automated Ligand Identification System (ALIS) Technology J. Med. Chem. (IF 7.446) Pub Date : 2022-06-15 Michael Garrigou, Bérengère Sauvagnat, Ruchia Duggal, Nicole Boo, Pooja Gopal, Jennifer M. Johnston, Anthony Partridge, Tomi Sawyer, Kaustav Biswas, Nicolas Boyer
Macrocyclic peptides can disrupt previously intractable protein–protein interactions (PPIs) relevant to oncology targets such as KRAS. Early hits often lack cellular activity and require meticulous improvement of affinity, permeability, and metabolic stability to become viable leads. We have validated the use of the Automated Ligand Identification System (ALIS) to screen oncogenic KRASG12D (GDP) against
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Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis J. Med. Chem. (IF 7.446) Pub Date : 2022-06-15 Susheel J. Nara, Srinivas Jogi, Srinivas Cheruku, Sarkunam Kandhasamy, Firoz Jaipuri, Pavan Kalyan Kathi, Subba Reddy, Sanket Sarodaya, Erica M. Cook, Tao Wang, Doree Sitkoff, Karen A. Rossi, Max Ruzanov, Susan E. Kiefer, Javed A. Khan, Mian Gao, Satyanarayana Reddy, Sankara Sivaprasad LVJ, Ramola Sane, Kathy Mosure, Xiaoliang Zhuo, Gary G. Cao, Milinda Ziegler, Anthony Azzara, John Krupinski, Matthew
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Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors J. Med. Chem. (IF 7.446) Pub Date : 2022-06-15 Na Li, Hong Yang, Ke Liu, Liwei Zhou, Yuting Huang, Danyan Cao, Yanlian Li, Yaoliang Sun, Aisong Yu, Zhiyan Du, Feng Yu, Ying Zhang, Bingyang Wang, Meiyu Geng, Jian Li, Bing Xiong, Shilin Xu, Xun Huang, Tongchao Liu
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Two-Photon Photodynamic Therapy Targeting Cancers with Low Carboxylesterase 2 Activity Guided by Ratiometric Fluorescence J. Med. Chem. (IF 7.446) Pub Date : 2022-06-14 Karishma Kailass, Oleg Sadovski, Warren R. Zipfel, Andrew A. Beharry
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Rationally Designed Amanitins Achieve Enhanced Cytotoxicity J. Med. Chem. (IF 7.446) Pub Date : 2022-06-13 Mihajlo Todorovic, Paul Rivollier, Antonio A. W. L. Wong, Zhou Wang, Alla Pryyma, Tuan Trung Nguyen, Kayla C. Newell, Juliette Froelich, David M. Perrin
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Discovery of a Novel Small-Molecule Inhibitor Disrupting TRBP–Dicer Interaction against Hepatocellular Carcinoma via the Modulation of microRNA Biogenesis J. Med. Chem. (IF 7.446) Pub Date : 2022-06-13 Ting Peng, Yujiao He, Tao Wang, Jialing Yu, Xiaofang Ma, Zongyuan Zhou, Yuwen Sheng, Lingyu Li, Huipan Peng, Sheng Li, Jiawei Zou, Yi Yuan, Yongyun Zhao, Hailong Shi, Fu Li, Wanli Liu, Kaifeng Hu, Xiaoxia Lu, Guolin Zhang, Fei Wang
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Hematopoietic Progenitor Kinase 1 in Tumor Immunology: A Medicinal Chemistry Perspective J. Med. Chem. (IF 7.446) Pub Date : 2022-06-13 Qiangsheng Zhu, Nannan Chen, Xinjian Tian, Yeling Zhou, QiDong You, Xiaoli Xu
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Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis J. Med. Chem. (IF 7.446) Pub Date : 2022-06-13 Kevin J. Frankowski, Samarjit Patnaik, Chen Wang, Noel Southall, Dipannita Dutta, Soumitta De, Dandan Li, Christopher Dextras, Yi-Han Lin, Marthe Bryant-Connah, Danielle Davis, Feijun Wang, Leah M. Wachsmuth, Pranav Shah, Jordan Williams, Md Kabir, Edward Zhu, Bolormaa Baljinnyam, Amy Wang, Xin Xu, John Norton, Marc Ferrer, Steve Titus, Anton Simeonov, Wei Zheng, Lesley A. Mathews Griner, Ajit Jadhav
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Biotin-Targeted Au(I) Radiosensitizer for Cancer Synergistic Therapy by Intervening with Redox Homeostasis and Inducing Ferroptosis J. Med. Chem. (IF 7.446) Pub Date : 2022-06-10 Zhibin Yang, Sheng Huang, Yu Liu, Xingyu Chang, Yanshan Liang, Xi Li, Zhongren Xu, Shiyu Wang, Yunlong Lu, Yuan Liu, Wukun Liu
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Discovery of Aryloxyphenyl–Heptapeptide Hybrids as Potent and Selective Matrix Metalloproteinase-2 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis J. Med. Chem. (IF 7.446) Pub Date : 2022-06-10 Tomoki Takeuchi, Masato Hayashi, Tomoko Tamita, Yusaku Nomura, Naoki Kojima, Akiko Mitani, Takuya Takeda, Kosuke Hitaka, Yuki Kato, Masafumi Kamitani, Masashi Mima, Hidetoh Toki, Masahiko Ohkubo, Akiko Nozoe, Hiroyuki Kakinuma
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Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides J. Med. Chem. (IF 7.446) Pub Date : 2022-06-10 Guodong Liu, Ruilin Hou, Lijuan Xu, Xinqi Zhang, Jianyu Yan, Chengguo Xing, Ke Xu, Chunlin Zhuang
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Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors J. Med. Chem. (IF 7.446) Pub Date : 2022-06-10 Liwen Hua, Qiuyue Zhang, Xinyue Zhu, Ruoning Wang, Qidong You, Lei Wang
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Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity J. Med. Chem. (IF 7.446) Pub Date : 2022-06-10 Zenichi Ikeda, Keiko Kakegawa, Fumiaki Kikuchi, Sachiko Itono, Hideyuki Oki, Hiroaki Yashiro, Hideyuki Hiyoshi, Kazue Tsuchimori, Kenichi Hamagami, Masanori Watanabe, Masako Sasaki, Youko Ishihara, Kimio Tohyama, Tomoyuki Kitazaki, Tsuyoshi Maekawa, Minoru Sasaki
To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional carboxylic acid moiety to obtain an extra interaction with enteropeptidase, yielding 2a. The oral administration of 2a
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Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1 J. Med. Chem. (IF 7.446) Pub Date : 2022-06-08 Ina Pöhner, Antonio Quotadamo, Joanna Panecka-Hofman, Rosaria Luciani, Matteo Santucci, Pasquale Linciano, Giacomo Landi, Flavio Di Pisa, Lucia Dello Iacono, Cecilia Pozzi, Stefano Mangani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Nuno Santarem, Anabela Cordeiro-da-Silva, Maria P. Costi, Alberto Venturelli, Rebecca C. Wade
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a
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Discovery of Clinical Candidate NTQ1062 as a Potent and Bioavailable Akt Inhibitor for the Treatment of Human Tumors J. Med. Chem. (IF 7.446) Pub Date : 2022-06-09 Changyou Ma, Jian Wu, Lei Wang, Xiaojun Ji, Yebin Wu, Lei Miao, Donghui Chen, Linlin Zhang, Youzhi Wu, Haiwei Feng, Ying Tang, Qiuhua Zhou, Junjie Pei, Xule Yang, Dan Xu, Qidong You, Yuan Xie
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Studying Lipophilicity Trends of Phosphorus Compounds by 31P-NMR Spectroscopy: A Powerful Tool for the Design of P-Containing Drugs J. Med. Chem. (IF 7.446) Pub Date : 2022-06-09 Ishay Columbus, Lee Ghindes-Azaria, Ravit Chen, Lea Yehezkel, Orit Redy-Keisar, Gil Fridkin, Dafna Amir, Daniele Marciano, Eyal Drug, Eytan Gershonov, Ziv Klausner, Sigal Saphier, Shlomi Elias, Alexander Pevzner, Yoav Eichen, Galit Parvari, Boris Smolkin, Yossi Zafrani
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Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma J. Med. Chem. (IF 7.446) Pub Date : 2022-06-07 Jingyu Zhang, Jinxin Che, Xiaomin Luo, Mingfei Wu, Weijuan Kan, Yuheng Jin, Hanlin Wang, Ao Pang, Cong Li, Wenhai Huang, Shenxin Zeng, Weihao Zhuang, Yizhe Wu, Yongjin Xu, Yubo Zhou, Jia Li, Xiaowu Dong
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Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position J. Med. Chem. (IF 7.446) Pub Date : 2022-06-08 Daniil V. Spector, Kirill G. Pavlov, Roman A. Akasov, Alexander N. Vaneev, Alexander S. Erofeev, Petr V. Gorelkin, Vita N. Nikitina, Elena V. Lopatukhina, Alevtina S. Semkina, Kseniya Yu. Vlasova, Dmitrii A. Skvortsov, Vitaly A. Roznyatovsky, Nikolay V. Ul’yanovskiy, Ilya I. Pikovskoi, Sergey A. Sypalov, Anastasiia S. Garanina, Stepan S. Vodopyanov, Maxim A. Abakumov, Yulia L. Volodina, Alina A. Markova
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Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras J. Med. Chem. (IF 7.446) Pub Date : 2022-06-08 Xufen Yu, Meng Cheng, Kaylene Lu, Yudao Shen, Yue Zhong, Jing Liu, Yue Xiong, Jian Jin
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Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects J. Med. Chem. (IF 7.446) Pub Date : 2022-06-06 Meng-Xing Huang, Yi-Jing Tian, Chuan Han, Run-Duo Liu, Xi Xie, Yijun Yuan, Yi-Yi Yang, Zhe Li, Jianwen Chen, Hai-Bin Luo, Yinuo Wu
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Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein J. Med. Chem. (IF 7.446) Pub Date : 2022-06-05 Lingxin Meng, Jianyang Fang, Liang Zhao, Tingting Wang, Pu Yuan, Zuoquan Zhao, Rongqiang Zhuang, Qin Lin, Haojun Chen, Xiaoyuan Chen, Xianzhong Zhang, Zhide Guo
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Phage Display Selected Cyclic Peptide Inhibitors of Kallikrein-Related Peptidases 5 and 7 and Their In Vivo Delivery to the Skin J. Med. Chem. (IF 7.446) Pub Date : 2022-06-02 Patrick Gonschorek, Alessandro Zorzi, Tamara Maric, Mathilde Le Jeune, Mischa Schüttel, Mathilde Montagnon, Rebeca Gómez-Ojea, Denis Patrick Vollmar, Chantal Whitfield, Luc Reymond, Vanessa Carle, Hitesh Verma, Oliver Schilling, Alain Hovnanian, Christian Heinis
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Effect of Chiral Purity on Adjuvanticity of Archaeol-Based Glycolipids J. Med. Chem. (IF 7.446) Pub Date : 2022-06-03 Sophie Régnier, Edmond Lam, Vinicio Vasquez, Camilo F. Martinez-Farina, Felicity C. Stark, Gerard Agbayani, Lise Deschatelets, Renu Dudani, Blair A. Harrison, Bassel Akache, Michael J. McCluskie, Usha D. Hemraz
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Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H1 Receptor J. Med. Chem. (IF 7.446) Pub Date : 2022-06-03 Zhi Yuan Kok, Leigh A. Stoddart, Sarah J. Mistry, Tamara A. M. Mocking, Henry F. Vischer, Rob Leurs, Stephen J. Hill, Shailesh N. Mistry, Barrie Kellam
The histamine H1 receptor (H1R) has recently been implicated in mediating cell proliferation and cancer progression; therefore, high-affinity H1R-selective fluorescent ligands are desirable tools for further investigation of this behavior in vitro and in vivo. We previously reported a H1R fluorescent ligand, bearing a peptide-linker, based on antagonist VUF13816 and sought to further explore structure–activity
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Selectivity through Targeted Protein Degradation (TPD) J. Med. Chem. (IF 7.446) Pub Date : 2022-06-03 Ariamala Gopalsamy
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Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors J. Med. Chem. (IF 7.446) Pub Date : 2022-06-03 Owen A. Davis, Kwai-Ming J. Cheung, Alfie Brennan, Matthew G. Lloyd, Matthew J. Rodrigues, Olivier A. Pierrat, Gavin W. Collie, Yann-Vaï Le Bihan, Rosemary Huckvale, Alice C. Harnden, Ana Varela, Michael D. Bright, Paul Eve, Angela Hayes, Alan T. Henley, Michael D. Carter, P. Craig McAndrew, Rachel Talbot, Rosemary Burke, Rob L. M. van Montfort, Florence I. Raynaud, Olivia W. Rossanese, Mirco Meniconi
To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core
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Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo J. Med. Chem. (IF 7.446) Pub Date : 2022-06-02 Rosemary Huckvale, Alice C. Harnden, Kwai-Ming J. Cheung, Olivier A. Pierrat, Rachel Talbot, Gary M. Box, Alan T. Henley, Alexis K. de Haven Brandon, Albert E. Hallsworth, Michael D. Bright, Hafize Aysin Akpinar, Daniel S. J. Miller, Dalia Tarantino, Sharon Gowan, Angela Hayes, Emma A. Gunnell, Alfie Brennan, Owen A. Davis, Louise D. Johnson, Selby de Klerk, Craig McAndrew, Yann-Vaï Le Bihan, Mirco
The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability
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Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands J. Med. Chem. (IF 7.446) Pub Date : 2022-06-02 Maria-Elena Liosi, Joseph A. Ippolito, Sean P. Henry, Stefan G. Krimmer, Ana S. Newton, Kara J. Cutrona, Rene A. Olivarez, Jyotidarsini Mohanty, Joseph Schlessinger, William L. Jorgensen
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Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist J. Med. Chem. (IF 7.446) Pub Date : 2022-06-02 Toru Iijima, Makoto Katoh, Kei Takedomi, Yasuo Yamamoto, Hidenori Akatsuka, Naritoshi Shirata, Akito Nishi, Misae Takakuwa, Yoshinori Watanabe, Hitomi Munakata, Naomi Koyama, Tomoko Ikeda, Taku Iguchi, Harutoshi Kato, Kohei Kikkawa, Takayuki Kawaguchi
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Structure-Based Discovery of Novel NH2-Biphenyl-Diarylpyrimidines as Potent Non-Nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Safety: From NH2-Naphthyl-Diarylpyrimidine to NH2-Biphenyl-Diarylpyrimidine J. Med. Chem. (IF 7.446) Pub Date : 2022-06-01 Xin Jin, Li-Min Zhao, Shuai Wang, Wen-Juan Huang, Yin-Xiang Zhang, Christophe Pannecouque, Erik De Clercq, Fen-Er Chen
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A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor J. Med. Chem. (IF 7.446) Pub Date : 2022-06-01 David A. Griffith, David J. Edmonds, Jean-Philippe Fortin, Amit S. Kalgutkar, J. Brent Kuzmiski, Paula M. Loria, Aditi R. Saxena, Scott W. Bagley, Clare Buckeridge, John M. Curto, David R. Derksen, João M. Dias, Matthew C. Griffor, Seungil Han, V. Margaret Jackson, Margaret S. Landis, Daniel Lettiere, Chris Limberakis, Yuhang Liu, Alan M. Mathiowetz, Jayesh C. Patel, David W. Piotrowski, David A. Price
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TocoDecoy: A New Approach to Design Unbiased Datasets for Training and Benchmarking Machine-Learning Scoring Functions J. Med. Chem. (IF 7.446) Pub Date : 2022-06-01 Xujun Zhang, Chao Shen, Ben Liao, Dejun Jiang, Jike Wang, Zhenxing Wu, Hongyan Du, Tianyue Wang, Wenbo Huo, Lei Xu, Dongsheng Cao, Chang-Yu Hsieh, Tingjun Hou
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Discovery of Small Molecules Simultaneously Targeting NAD(P)H:Quinone Oxidoreductase 1 and Nicotinamide Phosphoribosyltransferase: Treatment of Drug-Resistant Non-small-Cell Lung Cancer J. Med. Chem. (IF 7.446) Pub Date : 2022-05-31 Kuojun Zhang, Kaizhen Wang, Xiangyu Zhang, Zhenlong Qian, Wenbo Zhang, Xiao Zheng, Jiaying Wang, Yin Jiang, Wanheng Zhang, Zhiyu Lu, Haiping Hao, Sheng Jiang
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Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy J. Med. Chem. (IF 7.446) Pub Date : 2022-05-31 Wei Wang, Jiacheng He, Junjie Yang, Chan Zhang, Zhiyuan Cheng, Yao Zhang, Qiansen Zhang, Peili Wang, Shuowen Tang, Xin Wang, Mingyao Liu, Weiqiang Lu, Han-Kun Zhang
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Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents J. Med. Chem. (IF 7.446) Pub Date : 2022-05-31 Fang Lei, Yongxia Xiong, Yuqing Wang, Honghua Zhang, Ziyi Liang, Junfang Li, Yiyue Feng, Xiangyong Hao, Zhen Wang
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Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease J. Med. Chem. (IF 7.446) Pub Date : 2022-05-31 Chamandi S. Dampalla, Athri D. Rathnayake, Anushka C. Galasiti Kankanamalage, Yunjeong Kim, Krishani Dinali Perera, Harry Nhat Nguyen, Matthew J. Miller, Trent K. Madden, Hunter R. Picard, Hayden A. Thurman, Maithri M. Kashipathy, Lijun Liu, Kevin P. Battaile, Scott Lovell, Kyeong-Ok Chang, William C. Groutas
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Development of Lipo-γ-AA Peptides as Potent Antifungal Agents J. Med. Chem. (IF 7.446) Pub Date : 2022-05-30 Xing Zhang, Minghui Wang, Xiaodi Zhu, Yan Peng, Tiwei Fu, Chang-Hua Hu, Jianfeng Cai, Guojian Liao
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Platinum(IV) Prodrugs with Cancer Stem Cell Inhibitory Effects on Lung Cancer for Overcoming Drug Resistance J. Med. Chem. (IF 7.446) Pub Date : 2022-05-30 Xinyi Wang, Zhikun Liu, Yuanjiang Wang, Shaohua Gou
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Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma J. Med. Chem. (IF 7.446) Pub Date : 2022-05-29 Xiaomeng Zhang, Yazhou Wang, Jianfeng Ji, Dongjuan Si, Xueting Bao, Zhuangzhuang Yu, Yueyue Zhu, Liwen Zhao, Wei Li, Jian Liu
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Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease J. Med. Chem. (IF 7.446) Pub Date : 2022-05-27 Haozhou Tan, Yanmei Hu, Prakash Jadhav, Bin Tan, Jun Wang
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Correction to “Discovery and Structure-Based Optimization of Novel Atg4B Inhibitors for the Treatment of Castration-Resistant Prostate Cancer” J. Med. Chem. (IF 7.446) Pub Date : 2022-05-27 Yudai Kudo, Satoshi Endo, Mei Fujita, Atsumi Ota, Yuji O. Kamatari, Yoshimasa Tanaka, Takeshi Ishikawa, Hayato Ikeda, Takuya Okada, Naoki Toyooka, Naohiro Fujimoto, Toshiyuki Matsunaga, Akira Ikari
Figure 7. Docking model of 17. (A) Superimposed models of 17-docked Atg4B structure with proLC3 (PDB: 2Z0E). Atg4B, proLC3, and 17 are shown in light blue, green, and magenta, respectively. (B) Binding model of 17 in Atg4B. The residues within 4.0 Å from 17 are depicted with possible hydrogen bonds, and their distances are in angstroms. This article has not yet been cited by other publications. Figure
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Mind On Fire J. Med. Chem. (IF 7.446) Pub Date : 2022-05-26 Carolyn J. Straub
My thoughts were fast and frequent as I buzzed around campus my freshman year at college. Boring people were interesting, and there was not an audience I couldn’t captivate or be captivated by. My work fascinated me, and I threw myself into causes heedlessly. But as my thoughts raced ahead, they became frenzied, bringing confusion instead of clarity. The line between fantasy and reality became distorted
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Structure–Activity Relationships of 8-Hydroxyquinoline-Derived Mannich Bases with Tertiary Amines Targeting Multidrug-Resistant Cancer J. Med. Chem. (IF 7.446) Pub Date : 2022-05-25 Veronika F. S. Pape, Roberta Palkó, Szilárd Tóth, Miklós J. Szabó, Judit Sessler, György Dormán, Éva A. Enyedy, Tibor Soós, István Szatmári, Gergely Szakács
A recently proposed strategy to overcome multidrug resistance (MDR) in cancer is to target the collateral sensitivity of otherwise resistant cells. We designed a library of 120 compounds to explore the chemical space around previously identified 8-hydroxyquinoline-derived Mannich bases with robust MDR-selective toxicity. We included compounds to study the effect of halogen and alkoxymethyl substitutions
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Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein–Protein Interactions between DOT1L and MLL-AF9/MLL-ENL J. Med. Chem. (IF 7.446) Pub Date : 2022-05-25 Yinan Yuan, Lei Du, Rongliang Tan, Yifan Yu, Jinxin Jiang, Aihong Yao, Jiajun Luo, Rui Tang, Yibei Xiao, Haiying Sun
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Tuberculosis Drug Discovery: Challenges and New Horizons J. Med. Chem. (IF 7.446) Pub Date : 2022-05-25 Guilherme F. S. Fernandes, Andrew M. Thompson, Daniele Castagnolo, William A. Denny, Jean L. Dos Santos