Article
Biochemistry & Molecular Biology
Xiaoyi Zhang, Tong Zhao, Minghao Sun, Pei Li, Mengzhen Lai, Lingfeng Xie, Jiaying Chen, Jian Ding, Hua Xie, Jinpei Zhou, Huibin Zhang
Summary: Several small-molecule covalent inhibitors of KRASG12C have shown promising breakthroughs in treating KRAS mutant cancer. However, adaptive resistance may limit the clinical application of these inhibitors. The emerging PROTAC strategy offers complementary advantages and improves anti-tumor efficacy. Through protein degradation and anti-proliferative activities, novel KRASG12C-PROTACs have been demonstrated to effectively bind and degrade KRASG12C, surpassing the potency of AMG-510. Mechanistic studies indicate degradation effects through the ubiquitin-proteasome pathway. These findings support the use of PROTACs for degrading the oncogene KRASG12C and provide insights for optimizing the structure of KRASG12C-PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Qiaohua Qin, Ruifeng Wang, Qinglin Fu, Guoqi Zhang, Tianxiao Wu, Nian Liu, Ruicheng Lv, Wenbo Yin, Yin Sun, Yixiang Sun, Dongmei Zhao, Maosheng Cheng
Summary: FAK regulates tumor cell migration, invasion, survival, proliferation, and tumor stem cell regulation through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. The development of FAK PROTACs has become a hot research topic, and the designed PROTAC A13 showed promising inhibitory activity against FAK kinase and protein degradation, as well as improved anti-proliferative and anti-invasion effects. These findings suggest that PROTAC A13 could be a useful tool for studying the functions of FAK and a potential therapeutic agent.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Liang Jiang, Yuting Wang, Qian Li, Zhengchao Tu, Sihua Zhu, Sanfang Tu, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: A new class of selective Bcr-Abl(T315I) proteolysis-targeting chimeric degraders were designed, synthesized, and evaluated, with 7o exhibiting the most potent degradation efficacy and significant tumor regression in cell and animal models.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Chemistry, Medicinal
Yun Chen, Yi Ning, Gang Bai, Linjiang Tong, Tao Zhang, Jinpei Zhou, Huibin Zhang, Hua Xie, Jian Ding, Wenhu Duan
Summary: IRAK4 is a promising therapeutic target for diffuse large B-cell lymphoma, and a potent IRAK4 degrader was discovered to effectively inhibit downstream signaling. Eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Hualin Zhang, Ruliang Xie, Hawaa AI-furas, Yupeng Li, Qingxia Wu, Jian Li, Fang Xu, Tianfeng Xu
Summary: A series of EGFR proteolysis-targeting chimeras (PROTACs) were designed and synthesized to induce degradation of EGFR C797S mutant in resistant non-small cell lung cancer patients, with compound 6h showing promising degradation and antiproliferation activity.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Peng Wang, Huajian Zhu, Jianmin Liu, Shaowen Xie, Shengtao Xu, Yu Chen, Jing Xu, Yuqing Zhao, Zheying Zhu, Jinyi Xu
Summary: Protopanoxadiol, an active ingredient derived from Panax ginseng, has shown anti-tumor activity. A new series of AD-1 derivatives were designed and synthesized using PROTAC technology, aiming to improve the limited efficacy of AD-1. One representative compound, A05, exhibited potent anti-proliferative activity against A549 cells and was able to disrupt the interactions between p53 and MDM2, leading to apoptotic death. In vivo assays further demonstrated that compound A05 had anti-proliferative and anti-metastatic activities in a zebrafish tumor xenograft model. These findings suggest that AD-1 based PROTACs targeting MDM2 degradation have promising effects for lung cancer treatment.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Teja Ram, Ankit Kumar Singh, Prateek Pathak, Adarsh Kumar, Harshwardhan Singh, Maria Grishina, Jurica Novak, Pradeep Kumar
Summary: MEK mutations are common in various types of cancer, and the design of compounds with structural resemblance to FDA-approved MEK inhibitors has shown promise. Through chemical synthesis and computational studies, compound S15 was found to be the most potent against cancer cells, while compounds S1 and S5 were comparable to the standard drug trametinib.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Yin Sun, Ruifeng Wang, Yu Sun, Lin Wang, Yanli Xue, Jingkai Wang, Tianxiao Wu, Wenbo Yin, Qiaohua Qin, Yixiang Sun, Dongmei Zhao, Maosheng Cheng
Summary: The intracellular non-receptor tyrosine protein kinase Focal adhesion kinase (FAK) plays a crucial role in tumor survival, invasion, metastasis, and angiogenesis. The study demonstrates the importance of addressing both FAK kinase and scaffolding functions and introduces the use of PROTAC technology to simultaneously eliminate these functions. The novel FAK PROTAC B5 exhibits potent affinity and degradation activity against FAK, as well as powerful antiproliferative effects and inhibition of cell migration and invasion. The results suggest that PROTAC B5 holds promise as a lead compound for cancer drug discovery.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Aiping Chen, Yue Zhong, Yunxiao Liu, Zhancheng Xie, Hanyu Wu, Wei Shi, Wenlong Huang, Renxiang Tan, Hai Qian
Summary: The abnormal activation of BRD4 accelerates the progression of acute myeloid leukemia (AML). A range of small-molecule PROTACs were rationally designed to degrade BRD4 mediated by the E3 ubiquitin ligase CRBN. Among them, B24 exhibited remarkable BRD4 degradation and excellent anti-proliferative activities in MV4-11 cells, surpassing the effect of the BRD4 inhibitor ( +)-JQ-1. B24 also induced cell apoptosis and inhibited cell proliferation by down-regulating c-Myc and up-regulating Bax.
CHINESE CHEMICAL LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Yang Liu, Mengzhu Zheng, Zhilu Ma, Yirong Zhou, Junfeng Huo, Wenbo Zhang, Yu Liu, Yuanyuan Guo, Xuechen Zhou, Hua Li, Lixia Chen
Summary: Inhibitors targeting immune checkpoint provide a promising anticancer therapy by reversing immunosuppression and enhancing immune cell lethality to tumor cells. This study reports the development of PROTAC-based PD-L1 degraders that improve T cell killing activity against melanoma. Among the designed degraders, CRBN-ligand-based compound BMS-37-C3 shows the most potent activity in degrading PD-L1 and enhancing T cell killing ability.
CHINESE CHEMICAL LETTERS
(2023)
Article
Pharmacology & Pharmacy
Yiqing Yang, Tongke Tang, Xiaolu Li, Thomas Michel, Liqin Ling, Zhenghui Huang, Maruthi Mulaka, Yue Wu, Hongying Gao, Liguo Wang, Jing Zhou, Brigitte Meunier, Hangjun Ke, Lubin Jiang, Yu Rao
Summary: This study identified a novel multi-targeting antimalarial molecule RYL-581 through structure-based drug design, which binds to multiple protein binding sites of Plasmodium falciparum. The compound effectively kills various drug-resistant strains in vitro and exhibits good solubility as well as in vivo activity, suggesting its potential in future drug discovery projects targeting membrane-associated targets.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Biochemistry & Molecular Biology
Mengyuan Ding, Yingying Shao, Danwen Sun, Suorina Meng, Yi Zang, Yubo Zhou, Jia Li, Wei Lu, Shulei Zhu
Summary: This study designed and synthesized a series of small molecule BRD4 PROTACs, among which 8b could effectively degrade BRD4 and has the potential for treating related diseases such as leukemia, multiple myeloma, and pulmonary fibrosis.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Plant Sciences
Wang Wang, Yang Liu, Liangliang Xiong, Dejuan Sun, Hui Wang, Zhuorui Song, Yutong Li, Hua Li, Lixia Chen
Summary: Lathyrol, a core scaffold structure of lathyrane diterpenoids, has been found to possess potent anti-inflammatory activity. Researchers designed and synthesized 15 derivatives based on this structure. Compound 13 showed inhibitory activity against LPS-induced NO production in RAW264.7 cells with low cytotoxicity. It also effectively degraded the MAFF protein and activated the Keap1/Nrf2 pathway, leading to inhibition of NF -KB expression, blockade of its nuclear translocation, and activation of autophagy in LPS-induced RAW264.7 cells. Compound 13 could potentially be a promising anti-inflammatory agent.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Chemistry, Medicinal
Dingqiang Fu, Yi Yuan, Fengming Qin, Yan Xu, Xin Cui, Guangxun Li, Shaohua Yao, Yun Deng, Zhuo Tang
Summary: This study designed and synthesized a series of degraders using PROTAC technology that directly targeted human tyrosinase, with the best PROTAC TD9 showing promising results in inducing tyrosinase degradation and highlighting the potential for treating tyrosinase-related disorders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Shulei Zhu, Jieyu Liu, Donghuai Xiao, Peipei Wang, Jingkun Ma, Xiaobei Hu, Jingfeng Fu, Yubo Zhou, Jia Li, Wei Lu
Summary: This study reports a novel Wee1 degrader based on PROTAC technology, which effectively degrades cellular Wee1 protein and has potential applications in cancer therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Gangadhara Gangadhara, Goran Dahl, Thomas Bohnacker, Rebecca Rae, Jenny Gunnarsson, Stefan Blaho, Linda Oster, Helena Lindmark, Kostas Karabelas, Nils Pemberton, Christian Tyrchan, Mickael Mogemark, Matthias P. Wymann, Roger L. Williams, Matthew W. D. Perry, Tineke Papavoine, Jens Petersen
NATURE CHEMICAL BIOLOGY
(2019)
Article
Cell Biology
Engin Baturcam, Stefan Vollmer, Holger Schluter, Rose A. Maciewicz, Nisha Kurian, Outi Vaarala, Stephan Ludwig, Danen Mootoosamy Cunoosamy
CELL COMMUNICATION AND SIGNALING
(2019)
Article
Respiratory System
Nisha Kurian, Taylor S. Cohen, Lisa Oberg, Erica De Zan, Gabriel Skogberg, Stefan Vollmer, Engin Baturcam, Petter Svanberg, Britta Bonn, Paul D. Smith, Outi Vaarala, Danen M. Cunoosamy
INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
(2019)
Article
Biochemistry & Molecular Biology
Leire Iralde-Lorente, Giusy Tassone, Letizia Clementi, Lorenzo Franci, Claire C. Munier, Ylenia Cau, Mattia Mori, Mario Chiariello, Adriano Angelucci, Matthew W. D. Perry, Cecilia Pozzi, Stefano Mangani, Maurizio Botta
ACS CHEMICAL BIOLOGY
(2020)
Article
Pharmacology & Pharmacy
Claire C. Munier, Christian Ottmann, Matthew W. D. Perry
Summary: The 14-3-3 proteins play crucial roles in regulating the inflammatory response at genetic, molecular, and cellular levels. They affect key components of the immune response and can lead to clinical syndromes when their recognition processes are disrupted. Abnormal levels of 14-3-3 contribute to undesirable immune responses and chronic inflammatory conditions.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Chemistry, Medicinal
Matthew W. D. Perry, Karin Bjorhall, Peter Bold, Mikael Brulls, Ulf Borjesson, Johan Carlsson, Hui-Fang Amy Chang, Yunhua Chen, Anders Eriksson, Britt-Marie Fihn, Rebecca Fransson, Linda Fredlund, Hongbin Ge, Haijuan Huang, Kostas Karabelas, Eva Lamm Bergstrom, Sarah Lever, Helena Lindmark, Mickael Mogemark, Antonios Nikitidis, Anna-Pia Palmgren, Nils Pemberton, Jens Petersen, Mio Rodrigo Blomqvist, Reed W. Smith, Matthew J. Thomas, Victoria Ullah, Christian Tyrchan, Tiiu Wennberg, Annika Westin Eriksson, Wenzhen Yang, Shuchun Zhao, Linda Oster
Summary: Starting from previously described PI3K gamma inhibitors, exploration of structure-activity relationships led to the discovery of highly potent dual PI3K gamma delta inhibitors. The optimized compound, AZD8154, demonstrated efficacy in allergic asthma models and showed long duration of action in the lung with low systemic exposure and high selectivity against off-targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biotechnology & Applied Microbiology
Bart Vanhaesebroeck, Matthew W. D. Perry, Jennifer R. Brown, Fabrice Andre, Klaus Okkenhaug
Summary: Overactive PI3K is a frequently activated pathway in cancer, but therapeutic PI3K pathway inhibitors face challenges such as poor drug tolerance and resistance. Several targeted PI3K inhibitors have received regulatory approval, and their potential in cancer immunotherapy has been highlighted.
NATURE REVIEWS DRUG DISCOVERY
(2021)
Correction
Biotechnology & Applied Microbiology
Bart Vanhaesebroeck, Matthew W. D. Perry, Jennifer R. Brown, Fabrice Andre, Klaus Okkenhaug
NATURE REVIEWS DRUG DISCOVERY
(2021)
Article
Chemistry, Medicinal
Matthew W. D. Perry, Ulf Borjesson, Antonios Nikitidis, Christian Tyrchan
Summary: Contrary to expectations, N-aryl pyrrolidinones (and isosteric imidazolinones and oxazolinones) have higher lipophilicity and lower solubility than corresponding piper-idinones (tetrahydropyrimidinones and oxazinones). The observed effects are driven by a subtle interplay of steric and electronic effects, resulting in different conformations for the two classes of compounds.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Cell Biology
Sambit K. Nanda, Stefan Vollmer, Ana B. Perez-Oliva
Summary: This review summarizes classical post-translational modifications (PTMs) such as phosphorylation, ubiquitylation, and SUMOylation of the different components of NLRP3 and other emerging inflammasomes. The importance of these modifications in the biology, function, and regulation of these multiprotein complexes in various immune processes and human diseases is highlighted. Less-studied modifications and disease-associated mutations affecting PTMs are also discussed. The review concludes by emphasizing how a deeper understanding of different PTMs can contribute to the development of biomarkers and identification of novel drug targets for diseases associated with inflammasome malfunctioning.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Jakob S. Pallesen, Claire C. Munier, Francesco Bosica, Sebastian A. Andrei, Karl Edman, Anders Gunnarsson, Giuseppina La Sala, Okky Dwichandra Putra, Sonja Srdanovic, Andrew J. Wilson, Lisa Wissler, Christian Ottmann, Matthew W. D. Perry, Gavin O'Mahony
Summary: The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids. GR is also regulated through protein-protein interactions (PPIs) with adapter proteins 14-3-3 outside the steroid-binding site, providing insights into noncanonical GR signaling and enabling the development of novel GR modulators.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Hongtao Zhao, Jonas Branalt, Matthew Perry, Christian Tyrchan
Summary: It is well-known in medicinal chemistry that optimizing the potency of a small molecule at a macromolecular target requires compatibility between the ligand and target. This study focuses on the role of allylic strain in controlling conformational preferences. We examine various systems, such as benzylic positions, amides, N-aryl groups, aryl ethers, and nucleotides, and demonstrate how allylic strain has been utilized in drug discovery and can be prospectively used in the design process to influence conformation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Claire C. Munier, Leonardo De Maria, Karl Edman, Anders Gunnarsson, Marianna Longo, Carol MacKintosh, Saleha Patel, Arjan Snijder, Lisa Wissler, Luc Brunsveld, Christian Ottmann, Matthew W. D. Perry
Summary: The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that has a central role in inflammation and is modulated through protein-protein interactions. Key phosphorylation sites on the GR were identified, along with the responsible kinases, MINK1 and Rho-associated protein kinase 1. The study highlights MINK1 and the GR-14-3-3 axis as potential targets for future therapeutic interventions.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
