Article
Chemistry, Medicinal
Chungen Li, Yuanyuan Qiao, Xia Jiang, Lianchao Liu, Yang Zheng, Yudi Qiu, Caleb Cheng, Fengtao Zhou, Yang Zhou, Weixue Huang, Xiaomei Ren, Yuzhuo Wang, Zhen Wang, Arul M. Chinnaiyan, Ke Ding
Summary: Researchers have discovered a first-in-class PIKfyve degrader, PIK5-12d, which can effectively degrade PIKfyve protein and inhibit the growth of prostate cancer cells. It provides a valuable chemical tool for exploring PIKfyve-based targeted therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Yuan Pei, Jingfeng Fu, Yunkai Shi, Mengmeng Zhang, Guanghao Luo, Xiaomin Luo, Ning Song, Tian Mi, Yaxi Yang, Jia Li, Yubo Zhou, Bing Zhou
Summary: The selective degradation of USP7 using a PROTAC has shown promising results in inhibiting the growth of p53 mutant cancer cells, providing a potential therapeutic strategy for p53 mutant cancers.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Pharmacology & Pharmacy
Yongxi Liang, Delin Min, Hulin Fan, Kunlin Liu, Juchuanli Tu, Xueyan He, Bingjie Liu, Lu Zhou, Suling Liu, Xun Sun
Summary: Triple-negative breast cancer (TNBC) is a highly malignant and poor-prognosis disease. Annexin A3 (ANXA3) is a potential prognostic biomarker with a strong correlation to poor prognosis in patients. Researchers have discovered a first-in-class ANXA3-targeted small molecule (R)-SL18, which has shown excellent anti-proliferative and anti-invasive activities in TNBC cells. (R)-SL18 directly binds to ANXA3 and increases its ubiquitination, leading to ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 demonstrates safe and effective therapeutic potency in a TNBC patient-derived xenograft model with high ANXA3 expression. Furthermore, (R)-SL18 can reduce the level of beta-catenin and inhibit the Wnt/beta-catenin signaling pathway in TNBC cells. Overall, this data suggests that targeting the degradation of ANXA3 with (R)-SL18 has the potential to be a treatment strategy for TNBC.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Chemistry, Multidisciplinary
Jinmin Miao, Jiajun Dong, Yiming Miao, Yunpeng Bai, Zihan Qu, Brenson A. Jassim, Bo Huang, Quyen Nguyen, Yuan Ma, Allison A. Murray, Jinyue Li, Philip S. Low, Zhong-Yin Zhang
Summary: In this study, researchers discovered the first highly potent and selective TC-PTP degrader called TP1L, which can induce degradation of TC-PTP and enhance T-cell signaling and tumor killing efficacy.
Article
Chemistry, Medicinal
Qingna Jiang, Minghai Fu, Yuanling Tang, Ge Li, Guihui Tu, Xinhua Wu, Qiurong Wu, Xiuwang Huang, Jianhua Xu, Yang Liu, Lixian Wu
Summary: Heat shock protein 90 (Hsp90) is closely related to the stability and activation of tumor-related proteins. Compound X10g has been found to selectively degrade Hsp90a, which may provide a potential therapeutic strategy for breast cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Baishan Jiang, Yang Gao, Jianwei Che, Wenchao Lu, Ines H. Kaltheuner, Ruben Dries, Marian Kalocsay, Matthew J. Berberich, Jie Jiang, Inchul You, Nicholas Kwiatkowski, Kristin M. Riching, Danette L. Daniels, Peter K. Sorger, Matthias Geyer, Tinghu Zhang, Nathanael S. Gray
Summary: CDK12 is a promising therapeutic target for regulating DNA damage response genes transcription, but selective small molecule development has been hindered by its homology with other transcriptional CDKs. A CDK12-specific degrader, BSJ-4-116, was successfully designed and characterized, which selectively degraded CDK12 and resulted in premature cleavage and poly(adenylation) of DDR genes.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Santanu Hati, Marisa Zallocchi, Robert Hazlitt, Yuju Li, Sarath Vijayakumar, Jaeki Min, Zoran Rankovic, Sandor Lovas, Jian Zuo
Summary: This study introduced a new class of small molecules called PROTACs that can effectively degrade the CDK2 protein, with PROTAC-8 showing potential therapeutic activities. Experimental results demonstrated that PROTAC-8 can protect zebrafish from drug-induced auditory and neurotoxicity, indicating its promising role in treating hearing loss and cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Bowen Zhang, Chang Liu, Zhenqian Yang, Sai Zhang, Xiaolin Hu, Baohu Li, Mei Mao, Xiao Wang, Zhuoyue Li, Shumin Ma, Siqi Zhang, Chong Qin
Summary: We have developed small molecular PROTAC compounds that can effectively degrade AR-FL and AR-V7 proteins, and showed superior potency compared to the corresponding antagonists in prostate cancer cells. The representative compound BWA-522 achieved high oral bioavailability in both mice and beagle dogs. In a xenograft model study, BWA-522 demonstrated significant tumor growth inhibition, making it a promising AR-NTD PROTAC for treating AR-FL- and AR-V7-dependent tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lin Ma, Yingying Li, Ruixiang Luo, Yuhan Wang, Jiaqi Cao, Weitao Fu, Bolan Qian, Lei Zheng, Longguang Tang, Xinting Lv, Lulu Zheng, Guang Liang, Lingfeng Chen
Summary: The discovery of LC-MB12, a proteolysis-targeting chimeric molecule, offers a promising alternative strategy for targeting FGFR2 in cancer therapy. LC-MB12 shows selective degradation of FGFR2 and exhibits superior potency in suppressing FGFR signaling and inhibiting cell proliferation.
JOURNAL OF MEDICINAL CHEMISTRY
(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
Multidisciplinary Sciences
David S. Rogawski, Jing Deng, Hao Li, Hongzhi Miao, Dmitry Borkin, Trupta Purohit, Jiho Song, Jennifer Chase, Shuangjiang Li, Juliano Ndoj, Szymon Klossowski, EunGi Kim, Fengbiao Mao, Bo Zhou, James Ropa, Marta Z. Krotoska, Zhuang Jin, Patricia Ernst, Xiaomin Feng, Gang Huang, Kenichi Nishioka, Samantha Kelly, Miao He, Bo Wen, Duxin Sun, Andrew Muntean, Yali Dou, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka
Summary: The study developed small molecule inhibitors of the ASH1L histone methyltransferase, which bind to the autoinhibitory loop region in the SET domain. The lead compound AS-99 demonstrated on-target activity in leukemia cells by inducing apoptosis and differentiation, and reducing leukemia burden in vivo.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Simone Bonazzi, Eva d'Hennezel, Rohan E. J. Beckwith, Lei Xu, Aleem Fazal, Anna Magracheva, Radha Ramesh, Artiom Cernijenko, Brandon Antonakos, Hyo-eun C. Bhang, Roxana Garcia Caro, Jennifer S. Cobb, Elizabeth Ornelas, Xiaolei Ma, Charles A. Wartchow, Matthew C. Clifton, Ry R. Forseth, Bethany Hughes Fortnam, Hongbo Lu, Alfredo Csibi, Jennifer Tullai, Seth Carbonneau, Noel M. Thomsen, Jay Larrow, Barbara Chie-Leon, Dominik Hainzl, Yi Gu, Darlene Lu, Matthew J. Meyer, Dylan Alexander, Jacqueline Kinyamu-Akunda, Catherine A. Sabatos-Peyton, Natalie A. Dales, Frederic J. Zecri, Rishi K. Jain, Janine Shulok, Y. Karen Wang, Karin Briner, Jeffery A. Porter, John A. Tallarico, Jeffrey A. Engelman, Glenn Dranoff, James E. Bradner, Michael Visser, Jonathan M. Solomon
Summary: Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. The selective molecular glue degrader NVP-DKY709, which spares IKZF1/3, has been discovered and is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.
CELL CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Emily J. Hanan, Marie-Gabrielle Braun, Robert A. Heald, Calum MacLeod, Connie Chan, Saundra Clausen, Kyle A. Edgar, Charles Eigenbrot, Richard Elliott, Nicholas Endres, Lori S. Friedman, Emily Gogol, Xiao-Hui Gu, Rebecca Hong Thibodeau, Philip S. Jackson, James R. Kiefer, Jamie D. Knight, Michelle Nannini, Raman Narukulla, Amanda Pace, Jodie Pang, Hans E. Purkey, Laurent Salphati, Deepak Sampath, Stephen Schmidt, Steve Sideris, Kyung Song, Swathi Sujatha-Bhaskar, Mark Ultsch, Heidi Wallweber, Jianfeng Xin, SiewKuen Yeap, Amy Young, Yu Zhong, Steven T. Staben
Summary: This study optimized a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3K alpha that also induce selective degradation of the mutant p110 alpha protein. Structure-based design led to potent inhibitors with over 300-fold selectivity and further optimization of pharmacokinetic properties resulted in excellent in vivo efficacy. Clinical candidate GDC-0077 (inavolisib) is now being evaluated in a Phase III clinical trial for treating patients with PIK3CA-mutant breast cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jianzhang Yang, Yu Chang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, Josh Vo, Ingrid J. Apel, Cynthia Wang, Victoria Zhixuan Zeng, Yunhui Cheng, George Xiaoju Wang, Arul M. Chinnaiyan, Ke Ding
Summary: In this study, highly potent and selective dual CDK12/13 degraders were discovered using the PROTAC technology. The optimal compound 7f effectively degraded CDK12 and CDK13, and inhibited the proliferation of TNBC cell lines.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ning Sun, Md Kabir, Youngeun Lee, Ling Xie, Xiaoping Hu, Julia Velez, Xian Chen, H. Umit Kaniskan, Jian Jin
Summary: Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA/B inhibitors have been developed, but here, researchers report the discovery of a LDH proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105), which potently degrades LDHA and LDHB in a time- and ubiquitin-proteasome system dependent manner. Compound 22 shows stronger inhibitory effects on pancreatic cancer cell growth compared to the parent LDH inhibitor, and it is bioavailable in mice through intraperitoneal injection. Overall, compound 22 could be a valuable tool for studying the pathophysiological functions of LDH in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Xue-jing Shao, Sen-feng Xiang, Ying-qian Chen, Ning Zhang, Ji Cao, Hong Zhu, Bo Yang, Qian Zhou, Mei-dan Ying, Qiao-jun He
ACTA PHARMACOLOGICA SINICA
(2019)
Review
Pharmacology & Pharmacy
Yingqian Chen, Ji Cao, Ning Zhang, Bo Yang, Qiaojun He, Xuejing Shao, Meidan Ying
DRUG DISCOVERY TODAY
(2020)
Article
Pharmacology & Pharmacy
Xuejing Shao, Senfeng Xiang, Huarui Fu, Yingqian Chen, Aixiao Xu, Yujia Liu, Xiaotian Qi, Ji Cao, Hong Zhu, Bo Yang, Qiaojun He, Meidan Ying
PHARMACOLOGICAL RESEARCH
(2020)
Review
Pharmacology & Pharmacy
Wei Wang, Yingqian Chen, Aixiao Xu, Minyi Cai, Ji Cao, Hong Zhu, Bo Yang, Xuejing Shao, Meidan Ying, Qiaojun He
BRITISH JOURNAL OF PHARMACOLOGY
(2020)
Article
Biochemical Research Methods
Yan Liu, Chengting Luo, Ting Li, Wenhao Zhang, Zhaoyun Zong, Xiaohui Liu, Haiteng Deng
Summary: The study demonstrates that NMNH is a potent enhancer of NAD(+) and suppresses glycolysis, the TCA cycle, and cell growth. NMNH, produced through a chemical method, is more effective than NMN in increasing NAD(+) levels in vivo and in vitro, mediated by NMNAT.
JOURNAL OF PROTEOME RESEARCH
(2021)
Review
Pharmacology & Pharmacy
Yingqian Chen, Runzhi Liu, Wei Wang, Chen Wang, Ning Zhang, Xuejing Shao, Qiaojun He, Meidan Ying
Summary: Osteosarcoma, a highly malignant tumor with widespread genetic abnormalities, can be stratified into molecular subtypes for targeted therapy. Molecular classification based on genetic characteristics helps in achieving better therapeutic responses and moving towards personalized medicine.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Xuejing Shao, Yingqian Chen, Aixiao Xu, Danyan Xiang, Wei Wang, Wenxin Du, Yunpeng Huang, Xingya Zhang, Minyi Cai, Zhimei Xia, Yi Wang, Ji Cao, Yan Zhang, Bo Yang, Qiaojun He, Meidan Ying
Summary: Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RAR alpha, which disrupts the construction of PML nuclear bodies (NBs). The disrupted NB assembly in APL is caused by neddylation-induced aberrant phase separation of PML/RAR alpha. Deneddylation restores the phase separation process, suppresses leukemogenesis, and can be targeted for APL eradication.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Pharmacology & Pharmacy
Xuejing Shao, Yingqian Chen, Wei Wang, Wenxin Du, Xingya Zhang, Minyi Cai, Shaowei Bing, Ji Cao, Xiaojun Xu, Bo Yang, Qiaojun He, Meidan Ying
Summary: This study reveals a DUB-involved mechanism in regulating the stability of PML/RARα and develops a novel pharmacological approach to degrade PML/RARα by inhibiting DUB. The key DUB involved in this mechanism is identified as ovarian tumor protease YOD1. Inhibition of YOD1 promotes the degradation of PML/RARα and effectively inhibits the growth of APL cells.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Biochemical Research Methods
Ting Li, Hong Qu, Haibo Ding, Haiteng Deng, Yuling Chen
Summary: This study focused on profiling proteome changes in plasma before and after ART to identify molecular pathways affected by ART. The results showed upregulation and downregulation of specific proteins in response to ART, as well as potential targets related to CD4(+) T-cell recovery.
PROTEOMICS CLINICAL APPLICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Changmei Yang, Tianxiang Wang, Songbiao Zhu, Zhaoyun Zong, Chengting Luo, Yujiao Zhao, Jing Liu, Ting Li, Xiaohui Liu, Chongdong Liu, Haiteng Deng
Summary: Nicotinamide N-methyltransferase (NNMT) is overexpressed in cancer cells, leading to reduced levels of NAD+ and SAM, and activation of the STAT3 signaling pathway. Additionally, NNMT promotes inflammatory responses through the activation of the STAT3/IL1 beta/PGE2 axis, which further enhances cell growth, migration, epithelial-mesenchymal transition (EMT), and chemoresistance.
Review
Chemistry, Multidisciplinary
Chaoguo Cao, Ming He, Liguo Wang, Yuna He, Yu Rao
Summary: Proteolysis targeting chimeras (PROTACs) technology utilizes small molecules to induce ubiquitin-dependent degradation of proteins, offering a promising therapeutic strategy. However, the design and optimization of PROTACs face challenges, with a trial-and-error approach based on experience being the current general strategy. This review summarizes the principles and strategies for PROTACs design and optimization from the perspective of chemical structure design, and proposes potential future pathways for development.
CHEMICAL SOCIETY REVIEWS
(2022)
Article
Chemistry, Multidisciplinary
Liguo Wang, Yue Wu, Zhenzhen Li, Tianlong Lan, Xu Zhao, Wenxing Lv, Feng Shi, Xiangjian Luo, Yu Rao, Ya Cao
Summary: PEG5-Grifolin, as a water-miscible prodrug of grifolin, shows excellent stability and suppresses tumor growth by downregulating DNMT1 and reactivating the expression of multiple tumor suppressor genes in vivo. It may serve as a promising demethylation agent for DNMT1 associated diseases and be beneficial against various types of DNMT1 associated cancer.