Article
Chemistry, Multidisciplinary
Lan-song Xu, Su-xin Zheng, Liang-he Mei, Ke-xin Yang, Ya-fang Wang, Qiang Zhou, Xiang-tai Kong, Ming-yue Zheng, Hua-liang Jiang, Cheng-ying Xie
Summary: A novel and highly potent KRAS(G12C) inhibitor, 143D, was identified through a structure-based and focused chemical library analysis. It showed comparable antitumor efficacy to AMG510 and MRTX849 and selectively inhibited cell proliferation by downregulating KRAS(G12C)-dependent signal transduction, inducing cell cycle arrest and apoptosis.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Chemistry, Medicinal
Danni Rao, Heng Li, Xuelian Ren, Yaoliang Sun, Cuiyun Wen, Mingyue Zheng, He Huang, Wei Tang, Shilin Xu
Summary: ZAP-70 signaling pathway is crucial in T cell development and immune response, making it a promising target for autoimmune disease treatment. The development of a selective and potent covalent inhibitor of ZAP-70 kinase domain shows promising inhibitory effects on T cell activation and inflammatory response.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Satoshi Inoue, Yoshinobu Yamane, Shuntaro Tsukamoto, Hiroshi Azuma, Satoshi Nagao, Norio Murai, Kyoko Nishibata, Sayo Fukushima, Kenji Ichikawa, Takayuki Nakagawa, Naoko Hata Sugi, Daisuke Ito, Yu Kato, Aya Goto, Dai Kakiuchi, Takashi Ueno, Junji Matsui, Tomohiro Matsushima
Summary: The study shows that receptors Axl and Mer in the tyrosine kinase family have a promotional effect on tumor cell survival and proliferation. Chronic inhibition of Mer may lead to retinal toxicity in mice. Through research, a dual inhibitor of Axl/Mer and an Axl-selective inhibitor were discovered, with the latter showing no retinal toxicity and in vivo anti-tumor effects in mice.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Anthony Mastracchio, Chunqiu Lai, Enrico Digiammarino, Damien B. Ready, Loren M. Lasko, Kenneth D. Bromberg, William J. McClellan, Debra Montgomery, Vlasios Manaves, Bailin Shaw, Mikkel Algire, Melanie J. Patterson, Chaohong C. Sun, Saul Rosenberg, Albert Lai, Michael R. Michaelides
Summary: The development of a covalent inhibitor targeting p300/CBP has been reported in this study, demonstrating selective binding to C1450. Mass spectrometry and kinetics experiments were used to confirm the covalent binding of the inhibitor, providing a unique tool for studying p300/CBP biology.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Ning Yang, Zhiya Fan, Shiyang Sun, Xiaotong Hu, Yaqiu Mao, Changkai Jia, Xu Cai, Tingting Xu, Bingkun Li, Yi Li, Luobing Han, Ting Wei, Xiaohong Qian, Weijie Qin, Pengyun Li, Zhibing Zheng, Song Li
Summary: A series of highly potent and selective KRAS(G12C) Proteolysis Targeting Chimeras (PROTACs) were developed, among which YN14 showed significant inhibition of KRAS(G12C)-dependent cancer cells growth and tumor regression in mice models. KRAS(G12C) degradation exhibited advantages in overcoming resistance and combination with other inhibitors showed synergistic efficacy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Jason G. Kettle, Sharan K. Bagal, Derek Barratt, Michael S. Bodnarchuk, Scott Boyd, Erin Braybrooke, Jason Breed, Doyle J. Cassar, Sabina Cosulich, Michael Davies, Nichola L. Davies, Chao Deng, Andrew Eatherton, Laura Evans, Lyman J. Feron, Shaun Fillery, Emma S. Gleave, Frederick W. Goldberg, Miguel A. Cortes Gonzalez, Carine Guerot, Afreen Haider, Stephanie Harlfinger, Rachel Howells, Anne Jackson, Peter Johnstrom, Paul D. Kemmitt, Alex Koers, Mikhail Kondrashov, Gillian M. Lamont, Scott Lamont, Hilary J. Lewis, Libin Liu, Megan Mylrea, Samuel Nash, Michael J. Niedbala, Alison Peter, Christopher Phillips, Kurt Pike, Piotr Raubo, Graeme R. Robb, Sarah Ross, Matthew G. Sanders, Magnus Schou, Iain Simpson, Oliver Steward
Summary: In this study, a structure-based drug design approach led to the identification of a drug candidate called AZD4747, which is a highly potent and selective inhibitor of KRAS(G12C). It has potential for treating KRAS(G12C)-positive tumors, including central nervous system metastases. AZD4747 has low clearance and high oral bioavailability in humans.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Tian Lu, Yong Li, Wenchao Lu, Twgm Spitters, Xueyu Fang, Jun Wang, Simian Cai, Jing Gao, Yanting Zhou, Zhe Duan, Huan Xiong, Liping Liu, Qi Li, Hualiang Jiang, Kaixian Chen, Hu Zhou, Hua Lin, Huijin Feng, Bing Zhou, Christopher L. Antos, Cheng Luo
Summary: The TEAD family proteins play crucial roles in controlling cell differentiation and organ size in the Hippo pathway. Subtype selective inhibitors have been identified, providing important chemical probes for the study of TEAD-related functions in development and diseases. The development of a novel TEAD1/3 covalent inhibitor and subsequent optimization led to the discovery of a selective TEAD3 inhibitor with significant activity.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Chemistry, Medicinal
Jason G. Kettle, Sharan K. Bagal, Sue Bickerton, Michael S. Bodnarchuk, Scott Boyd, Jason Breed, Rodrigo J. Carbajo, Doyle J. Cassar, Atanu Chakraborty, Sabina Cosulich, Iain Cumming, Michael Davies, Nichola L. Davies, Andrew Eatherton, Laura Evans, Lyman Feron, Shaun Fillery, Emma S. Gleave, Frederick W. Goldberg, Lyndsey Hanson, Stephanie Harlfinger, Martin Howard, Rachel Howells, Anne Jackson, Paul Kemmitt, Gillian Lamont, Scott Lamont, Hilary J. Lewis, Libin Liu, Michael J. Niedbala, Christopher Phillips, Radek Polanski, Piotr Raubo, Graeme Robb, David M. Robinson, Sarah Ross, Matthew G. Sanders, Michael Tonge, Rebecca Whiteley, Stephen Wilkinson, Junsheng Yang, Wenman Zhang
Summary: KRAS is a valuable and challenging drug target in oncology, and a specific mutation has made it druggable. The research introduces a structure-based drug design method and presents AZD4625 as a potential treatment for KRASG12C positive tumors. AZD4625 shows high potency and selectivity as a KRASG12C inhibitor, with favorable clearance and oral bioavailability in humans.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Qiangsheng Zhang, Xi Hu, Lu Li, Lidan Zhang, Guoquan Wan, Qiang Feng, Yongxia Zhu, Ningyu Wang, Zhihao Liu, Luoting Yu
Summary: SKLB-0335 displays high paralog-selectivity on EZH2 by targeting its unique Cys663, covalently binding to EZH2 at its S-adenosylmethionine (SAM) pocket and inhibiting H3K27Me3. This compound could serve as an effective chemical probe to further investigate the specific biological functions of EZH2.
CHEMICAL COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Xiaobao Fang, Chunxiao Liu, Kun Zhang, Wanping Yang, Zewen Wu, Shige Shen, Yule Ma, Xun Lu, Yadong Chen, Tao Lu, Qinghua Hu, Yulei Jiang
Summary: This study discovered a series of novel, potent, and selective covalent BTK inhibitors through structure-based drug design, among which compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel BTK inhibitor requiring further development for the treatment of autoimmune diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Edwige Lorthiois, Marc Gerspacher, Kim S. Beyer, Andrea Vaupel, Catherine Leblanc, Rowan Stringer, Andreas Weiss, Rainer Wilcken, Daniel A. Guthy, Andreas Lingel, Claudio Bomio-Confaglia, Rainer Machauer, Pascal Rigollier, Johannes Ottl, Dorothee Arz, Pascal Bernet, Gaelle Desjonqueres, Solene Dussauge, Malika Kazic-Legueux, Marie-Anne Lozac'h, Christophe Mura, Mickael Sorge, Milen Todorov, Nicolas Warin, Florence Zink, Hans Voshol, Frederic J. Zecri, Richard C. Sedrani, Nils Ostermann, Saskia M. Brachmann, Simona Cotesta
Summary: The rapid emergence of tumor resistance through RAS pathway reactivation has been reported. Therefore, the development of inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations is important. JDQ443 is a stable covalent KRASG12C inhibitor derived from structure-based drug design. It has shown PK/PD activity in vivo and dose-dependent antitumor activity in mouse models. JDQ443 is currently in clinical development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Yahong Liu, Ying Cheng, Gongchao Huang, Xiangying Xia, Xingkai Wang, Hongqi Tian
Summary: Tunlametinib is a novel MEK inhibitor with higher selectivity and anti-proliferation activity compared to current MEK inhibitors. It exhibits significant tumor suppression and cell cycle regulation in vivo. Furthermore, combination therapy of tunlametinib with other inhibitors or chemotherapeutic agents enhances the treatment response.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Ronan P. Hanley, David Y. Nie, John R. Tabor, Fengling Li, Amin Sobh, Chenxi Xu, Natalie K. Barker, David Dilworth, Taraneh Hajian, Elisa Gibson, Magdalena M. Szewczyk, Peter J. Brown, Dalia Barsyte-Lovejoy, Laura E. Herring, Gang Greg Wang, Jonathan D. Licht, Masoud Vedadi, Cheryl H. Arrowsmith, Lindsey I. James
Summary: Nuclear receptor-binding SET domain-containing 2 (NSD2) is involved in gene regulation by dimethylating lysine 36 of histone 3 (H3K36me2). UNC8153 is a novel NSD2-targeted degrader that effectively reduces NSD2 protein and H3K36me2 levels. It works by degrading NSD2 through a unique mechanism and has demonstrated positive effects on pathological phenotypes in multiple myeloma cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Oncology
Atanu Chakraborty, Lyndsey Hanson, David Robinson, Hilary Lewis, Sue Bickerton, Michael Davies, Radoslaw Polanski, Rebecca Whiteley, Alex Koers, James Atkinson, Tamara Baker, Ivan del Barco Barrantes, Giovanni Ciotta, Jason G. Kettle, Lukasz Magiera, Carla P. Martins, Alison Peter, Eleanor Wigmore, Zoe Underwood, Sabina Cosulich, Michael Niedbala, Sarah Ross
Summary: AZD4625 is a potent inhibitor of oncogenic KRASG12C with selective binding and inhibition. It has shown therapeutic potential in both cellular assays and animal models, making it a promising candidate for monotherapy or combination therapy for patients with KRASG12C mutant cancer.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Chemistry, Multidisciplinary
Yongfeng Tao, Jan G. Felber, Zhongyu Zou, Evert Njomen, Jarrett R. Remsberg, Daisuke Ogasawara, Chang Ye, Bruno Melillo, Stuart L. Schreiber, Chuan He, David Remillard, Benjamin F. Cravatt
Summary: This study discovered azetidine acrylamides that act as covalent inhibitors of human NSUN2 through targeting a conserved catalytic cysteine, showing high isotype selectivity and perturbing NSUN2-tRNA interactions and the m5C content of RNA in cancer cells.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Pharmacology & Pharmacy
Ruben de Kanter, Patricia N. Sidharta, Stphane Delahaye, Carmela Gnerre, Jerome Segrestaa, Stephan Buchmann, Christopher Kohl, Alexander Treiber
CLINICAL PHARMACOKINETICS
(2016)
Article
Chemistry, Medicinal
Martin H. Bolli, Cyrille Lescop, Magdalena Birker, Ruben de Kanter, Patrick Hess, Christopher Kohl, Oliver Nayler, Markus Rey, Patrick Sieber, Jorg Velker, Thomas Weller, Beat Steiner
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Medicinal
Cyrille Lescop, Claus Muller, Boris Mathys, Magdalena Birker, Ruben de Kanter, Christopher Kohl, Patrick Hess, Oliver Nayler, Markus Rey, Patrick Sieber, Beat Steiner, Thomas Weller, Martin H. Bolli
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Review
Pharmacology & Pharmacy
William Brian, Larry M. Tremaine, Million Arefayene, Ruben de Kanter, Raymond Evers, Yingying Guo, James Kalabus, Wen Lin, Cho-Ming Loi, Guangqing Xiao
Article
Medicine, General & Internal
Amelie Le Bihan, Ruben de Kanter, Inigo Angulo-Barturen, Christoph Binkert, Christoph Boss, Reto Brun, Ralf Brunner, Stephan Buchmann, Jeremy Burrows, Koen J. Dechering, Michael Delves, Sonja Ewerlingl, Santiago Ferrer, Christoph Fischli, Francisco Javier Gamo-Benito, Nina F. Gnadig, Bibia Heidmann, Maria Belen Jimenez-Diaz, Didier Leroy, Maria Santos Martinez, Solange Meyer, Joerg J. Moehrle, Caroline L. Ng, Rintis Noviyanti, Andrea Ruecker, Laura Maria Sanz, Robert W. Sauerwein, Christian Scheurer, Sarah Schleiferboeck, Robert Sinden, Christopher Snyder, Judith Straimer, Grennady Wirjanata, Jutta Marfurt, Ric N. Price, Thomas Weller, Walter Fischli, David A. Fidock, Martine Clozel, Sergio Wittlin
Article
Microbiology
Shirin Bruderer, Noemie Hurst, Ruben de Kanter, Tommaso Miraval, Thomas Pfeifer, Yves Donazzolo, Jasper Dingemanse
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2015)
Article
Chemistry, Medicinal
Claire-Lise Ciana, Romain Siegrist, Hamed Aissaoui, Leo Marx, Sophie Racine, Solange Meyer, Christoph Binkert, Ruben de Kanter, Christoph Fischli, Sergio Wittlin, Christoph Boss
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
Martin H. Bolli, Stefan Abele, Magdalena Birker, Roberto Bravo, Daniel Bur, Ruben de Kanter, Christopher Kohl, Julien Grimont, Patrick Hess, Cyrille Lescop, Boris Mathys, Claus Mueller, Oliver Nayler, Markus Rey, Michael Scherz, Gunther Schmidt, Juergen Seifert, Beat Steiner, Joerg Velker, Thomas Weller
JOURNAL OF MEDICINAL CHEMISTRY
(2014)
Article
Chemistry, Medicinal
Martin H. Bolli, Joerg Velker, Claus Mueller, Boris Mathys, Magdalena Birker, Roberto Bravo, Daniel Bur, Ruben de Kanter, Patrick Hess, Christopher Kohl, David Lehmann, Solange Meyer, Oliver Nayler, Markus Rey, Michael Scherz, Beat Steiner
JOURNAL OF MEDICINAL CHEMISTRY
(2014)
Article
Biochemical Research Methods
Inge A. M. de Graaf, Peter Olinga, Marina H. de Jager, Marjolijn T. Merema, Ruben de Kanter, Esther G. van de Kerkhof, Geny M. M. Groothuis
Article
Chemistry, Medicinal
Edwige Lorthiois, Marc Gerspacher, Kim S. Beyer, Andrea Vaupel, Catherine Leblanc, Rowan Stringer, Andreas Weiss, Rainer Wilcken, Daniel A. Guthy, Andreas Lingel, Claudio Bomio-Confaglia, Rainer Machauer, Pascal Rigollier, Johannes Ottl, Dorothee Arz, Pascal Bernet, Gaelle Desjonqueres, Solene Dussauge, Malika Kazic-Legueux, Marie-Anne Lozac'h, Christophe Mura, Mickael Sorge, Milen Todorov, Nicolas Warin, Florence Zink, Hans Voshol, Frederic J. Zecri, Richard C. Sedrani, Nils Ostermann, Saskia M. Brachmann, Simona Cotesta
Summary: The rapid emergence of tumor resistance through RAS pathway reactivation has been reported. Therefore, the development of inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations is important. JDQ443 is a stable covalent KRASG12C inhibitor derived from structure-based drug design. It has shown PK/PD activity in vivo and dose-dependent antitumor activity in mouse models. JDQ443 is currently in clinical development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Letter
Pharmacology & Pharmacy
Ruben de Kanter, Christopher Kohl
BIOPHARMACEUTICS & DRUG DISPOSITION
(2017)
Article
Pharmacology & Pharmacy
Alexander Treiber, Paeivi Aeaenismaa, Ruben de Kanter, Stephane Delahaye, Marianne Treher, Patrick Hess, Patricia Sidharta
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2014)