Article
Chemistry, Medicinal
Pengming Pan, Tongtong Geng, Zhongtang Li, Xuyang Ding, Mengyuan Shi, Yang Li, Yashuai Wang, Yuanyuan Shi, Jiaojiao Wu, Liang Zhong, Dengbo Ji, Zhongjun Li, Xiangbao Meng
Summary: ERK5, a key member of the mitogen-activated protein kinase family, is involved in tumor growth, migration, and angiogenesis. We developed a selective ERK5 degrader and found that its degradation did not directly affect tumor cell growth, but may be associated with tumor immunity and macrophage differentiation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Nis Halland, Friedemann Schmidt, Tilo Weiss, Ziyu Li, Jorg Czech, Joachim Saas, Danping Ding-Pfennigdorff, Matthias K. Dreyer, Carsten Strubing, Marc Nazare
Summary: A highly selective SGK1 inhibitor with optimized safety and pharmacokinetic profile for oral dosing has been identified as a potential disease-modifying agent for osteoarthritis.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Gisele Nishiguchi, Fatemeh Keramatnia, Jaeki Min, Yunchao Chang, Barbara Jonchere, Sourav Das, Marisa Actis, Jeanine Price, Divyabharathi Chepyala, Brandon Young, Kevin McGowan, P. Jake Slavish, Anand Mayasundari, Jamie A. Jarusiewicz, Lei Yang, Yong Li, Xiang Fu, Shalandus H. Garrett, James B. Papizan, Kiran Kodali, Junmin Peng, Shondra M. Pruett Miller, Martine F. Roussel, Charles Mullighan, Marcus Fischer, Zoran Rankovic
Summary: This study describes the design, synthesis, and screening of a large diverse library of thalidomide analogues against leukemia and medulloblastoma cell lines, leading to the discovery of potent GSPT1/2 degraders with selectivity over IMiD neosubstrates and high oral bioavailability in mice. Compound 6 (SJ6986) is proposed as a valuable tool for studying the role of GSPT1/2 and supports the utility of a diverse library of CRBN binders in targeting undruggable oncoproteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Camilla Scarpellini, Sophie Valembois, Kenneth Goossens, Mike Vadi, Caroline Lanthier, Greta Klejborowska, Pieter Van der Veken, Hans De Winter, Mathieu J. M. Bertrand, Koen Augustyns
Summary: RIPK1 is a key driver of inflammation and its activity indirectly promotes inflammation by triggering cell death. Researchers have optimized the structure of GSK'157 to develop a novel class of more selective RIPK1 inhibitors.
FRONTIERS IN CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Wenzhi Ji, Eric S. Wang, Theresa D. Manz, Jie Jiang, Katherine A. Donovan, Xianmixinuer Abulaiti, Eric S. Fischer, Lewis C. Cantley, Tinghu Zhang, Nathanael S. Gray
Summary: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), consisting of three members (alpha, beta, and gamma) in mammals, have attracted attention as potential therapeutic targets due to their involvement in regulating various vital cellular signaling pathways. Among them, PI5P4K gamma shows distinct expression patterns and has been implicated in cancer and neurodegenerative diseases. A novel PI5P4K gamma degrader, JWZ-1-80, has been developed and characterized, exhibiting potent degradation activity and selective targeting towards PI5P4K gamma via the ubiquitin-proteasome system, which makes it a valuable tool compound for further investigations on the biological functions of PI5P4K gamma.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Mingfeng Yu, Theodosia Teo, Yuchao Yang, Manjun Li, Yi Long, Stephen Philip, Benjamin Noll, Gary K. Heinemann, Sarah Diab, Preethi Eldi, Laychiluh Mekonnen, Abel T. Anshabo, Muhammed H. Rahaman, Robert Milne, John D. Hayball, Shudong Wang
Summary: CDK8 plays a crucial role in transcriptional regulation and its dysregulation is associated with various types of cancer. Inhibition of CDK8 with compound 38 showed potent anti-proliferative effects on acute myeloid leukaemia cells without systemic toxicity in preclinical studies. Further research on compound 38 as an anticancer agent is warranted.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Dennis X. Hu, Snahel Patel, Huifen Chen, Shumei Wang, Steven T. Staben, Yoana N. Dimitrova, Heidi Ackerly Wallweber, Joanna Y. Lee, Grace Ka Yan Chan, Christopher J. Sneeringer, Madeleine S. Prangley, John G. Moffat, Kai C. Wu, Leah K. Schutt, Laurent Salphati, Jodie Pang, Erin McNamara, Haochu Huang, Yong Chen, Yunli Wang, Wensheng Zhao, Junghyun Lim, Aditya Murthy, Michael Siu
Summary: A new series of dihydropyr-azolopyrazinone compounds have been identified as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. The study suggests that sustained inhibition of VPS34 kinase activity may not be well tolerated, and the selectivity of VPS34 inhibitors over PIK family kinases is crucial. This research may provide insights for avoiding targeting VPS34 in other ATP-competitive kinase programs.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Xufen Yu, Jia Xu, Yudao Shen, Kaitlyn M. Cahuzac, Kwang-Su Park, Brandon Dale, Jing Liu, Ramon E. Parsons, Jian Jin
Summary: In this study, we reported a potent AKT degrader MS21 and its structure-activity relationship (SAR) studies. Additionally, we discovered another VHL-recruiting AKT degrader MS143 with similar efficacy as MS21, as well as a novel CRBN-recruiting PROTAC MS5033. These compounds effectively degraded AKT by hijacking the ubiquitin-proteasome system and showed significant inhibition of cell growth in multiple cancer cell lines. Furthermore, they exhibited good plasma exposure levels in mice and were suitable for in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Darshan Joshi, Rajesh Bahekar, Shubhangi Soman, Pradip Jadav, Dipam Patel, Amitgiri Goswami, Jignesh Pethani, Jeevan Kumar, Jitendra Patel, Rajesh Sundar, Poonamgiri Goswami, Krishnarup Goshdastidar, Hoshang Patel, Ankit Patel, Debdutta Bandyopadhyay, Abhijit Chattarjee, Manoranjan Sharma, Mukul Jain, Ranjit Desai
Summary: In this study, novel structural optimizations were conducted to discover effective Bruton's Tyrosine Kinase (BTK) inhibitors for the treatment of autoimmune disorders. Compound 14b was identified as a potent and selective BTK inhibitor with improved oral bioavailability. It displayed strong efficacy in in vitro and in vivo assays, making it a viable therapeutic option for autoimmune disorders.
BIOORGANIC CHEMISTRY
(2023)
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
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
Reinad R. Abu Rabah, Anusha Sebastian, Srinivasulu Vunnam, Shaista Sultan, Hamadeh Tarazi, Hanan S. Anbar, Mahmoud K. Shehata, Seyed-Omar Zaraei, Sara M. Elgendy, Salma A. Al Shamma, Hany A. Omar, Taleb H. Al-Tel, Mohammed El-Gamal
Summary: The study reports on a new series of pyrazole derivatives with potential anticancer activity. Compound 1f showed the most potent anticancer activity against various cancer cell lines, even more potent than sorafenib and SP600125. Compounds 1b, 1c, and 1h demonstrated strong anti-proliferative activity against hepatocellular carcinoma cell lines. The study also discovered two potent JNK3 inhibitors, compounds 1c and 1f, with good inhibitory effects in whole-cell assays.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Cheng-Liang Zhu, Xiaomin Luo, Tian Tian, Zijian Rao, Hanlin Wang, Zhesheng Zhou, Tian Mi, Danni Chen, Yongjin Xu, Yizhe Wu, Jinxin Che, Yubo Zhou, Jia Li, Xiaowu Dong
Summary: This study successfully synthesized an AKT degrader B4, which efficiently degrades AKT protein and exhibits significant efficacy in anti-proliferation and inhibiting signaling pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
John M. Ketcham, Jacob Haling, Shilpi Khare, Vickie Bowcut, David M. Briere, Aaron C. Burns, Robin J. Gunn, Anthony Ivetac, Jon Kuehler, Svitlana Kulyk, Jade Laguer, J. David Lawson, Krystal Moya, Natalie Nguyen, Lisa Rahbaek, Barbara Saechao, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Laura Vegar, Darin Vanderpool, Xiaolun Wang, Larry Yan, Peter Olson, James G. Christensen, Matthew A. Marx
Summary: SOS1 is an important regulator of KRAS, and disrupting the SOS1:KRASG12C protein-protein interaction can increase the proportion of GDP-loaded KRASG12C. In this study, researchers designed and discovered MRTX0902, a potent and selective SOS1 binder that can disrupt the SOS1:KRASG12C interaction. Combining oral administration of MRTX0902 with MRTX849 has shown significant antitumor activity, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Danli Zhou, Yingying Zuo, Zhengying Pan
Summary: This study reports the development of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy, which holds great therapeutic potential for human autoimmune diseases and T-cell malignant lymphomas. Two representative compounds, 23 and 28, demonstrated potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays confirmed the high selectivity of compounds 23 and 28 as ITK degraders. Compound 28 exhibited efficient, rapid, and prolonged ITK degradation in mice, along with significant suppression of IL-2 secretion. It is the first effective and highly selective ITK degrader, serving as a valuable tool compound for further investigation of ITK degradation in human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Jie Li, Phillip M. Galbo, Weida Gong, Aaron J. Storey, Yi-Hsuan Tsai, Xufen Yu, Jeong Hyun Ahn, Yiran Guo, Samuel G. Mackintosh, Ricky D. Edmondson, Stephanie D. Byrum, Jason E. Farrar, Shenghui He, Ling Cai, Jian Jin, Alan J. Tackett, Deyou Zheng, Gang Greg Wang
Summary: This study reveals that the fusion gene ZMYND11-MBTD1 (ZM) induces AML in a subset of patients by activating the NuA4/TIP60 histone acetyltransferase complex. ZM directly regulates the expression of pro-leukemic genes, promoting the development of AML through sustaining an active chromatin state.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Xufen Yu, Jia Xu, Yudao Shen, Kaitlyn M. Cahuzac, Kwang-Su Park, Brandon Dale, Jing Liu, Ramon E. Parsons, Jian Jin
Summary: In this study, we reported a potent AKT degrader MS21 and its structure-activity relationship (SAR) studies. Additionally, we discovered another VHL-recruiting AKT degrader MS143 with similar efficacy as MS21, as well as a novel CRBN-recruiting PROTAC MS5033. These compounds effectively degraded AKT by hijacking the ubiquitin-proteasome system and showed significant inhibition of cell growth in multiple cancer cell lines. Furthermore, they exhibited good plasma exposure levels in mice and were suitable for in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Jun Wang, Xufen Yu, Weida Gong, Xijuan Liu, Kwang-Su Park, Anqi Ma, Yi-Hsuan Tsai, Yudao Shen, Takashi Onikubo, Wen-Chieh Pi, David F. Allison, Jing Liu, Wei-Yi Chen, Ling Cai, Robert G. Roeder, Jian Jin, Gang Greg Wang
Summary: The study reveals the noncanonical oncogenic roles of EZH2 in acute leukaemia, demonstrating its additional functions in binding cMyc and activating gene expression. To target the multifaceted tumorigenic functions of EZH2, the researchers developed a degrader, MS177, which effectively depletes both canonical and noncanonical complexes of EZH2 and shows a faster and more potent effect in suppressing cancer growth.
NATURE CELL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Dongxu Li, Xufen Yu, Jithesh Kottur, Weida Gong, Zhao Zhang, Aaron J. Storey, Yi-Hsuan Tsai, Hidetaka Uryu, Yudao Shen, Stephanie D. Byrum, Rick D. Edmondson, Samuel G. Mackintosh, Ling Cai, Zhijie Liu, Aneel K. Aggarwal, Alan J. Tackett, Jing Liu, Jian Jin, Gang Greg Wang
Summary: A new proteolysis targeting chimera (PROTAC) named MS40 has been developed to selectively degrade WDR5 and Ikaros, showing promising anti-cancer effects in MLL-rearranged leukemias.
Article
Multidisciplinary Sciences
Zhihong Ren, Arum Kim, Yu-Ting Huang, Wen-Chieh Pi, Weida Gong, Xufen Yu, Jun Qi, Jian Jin, Ling Cai, Robert G. Roeder, Wei-Yi Chen, Gang Greg Wang
Summary: Acute myeloid leukemias (AMLs) with NUP98-NSD1 or MLL-r have stemness-related gene signatures and poor prognosis. Inhibiting EZH2 enzymatic activity shows that PRC2 is crucial for tumorigenicity in NUP98-NSD1(+) AML, and Kdm5b is directly repressed by PRC2. Kdm5b not only suppresses AML growth but also attenuates the anti-AML effects of PRC2 inhibitors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Medicinal
Xufen Yu, Meng Cheng, Kaylene Lu, Yudao Shen, Yue Zhong, Jing Liu, Yue Xiong, Jian Jin
Summary: This study reports the discovery of two novel EGFR degraders that selectively degrade the mutant EGFR but not the wild-type EGFR through both ubiquitination/proteasome and autophagy/lysosome pathways. Mechanistic studies reveal that the mutant EGFR can effectively form EGFR-PROTAC-E3 ligase ternary complexes.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Jing Liu, Xufen Yu, He Chen, H. Umit Kaniskan, Ling Xie, Xian Chen, Jian Jin, Wenyi Wei
Summary: A platform named TF-DUBTAC has been developed to selectively stabilize tumor suppressor transcription factors through linking a DNA oligonucleotide to a covalent ligand of the deubiquitinase OTUB1. This method successfully stabilized FOXO3A, p53, and IRF3 in cells, providing a potential therapeutic means to suppress tumorigenesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Jun Wang, Kwang-Su Park, Xufen Yu, Weida Gong, H. Shelton Earp, Gang Greg Wang, Jian Jin, Ling Cai
Summary: This study reveals the non-canonical (co-)activator recruitment and gene activation functions of EZH2 in prostate cancer and suggests that EZH2-targeting PROTACs could be a potential therapeutic approach for aggressive prostate cancer.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biology
Wesley L. Cai, Jocelyn Fang-Yi Chen, Huacui Chen, Emily Wingrove, Sarah J. Kurley, Lok Hei Chan, Meiling Zhang, Anna Arnal-Estape, Minghui Zhao, Amer Balabaki, Wenxue Li, Xufen Yu, Ethan D. Krop, Yali Dou, Yansheng Liu, Jian Jin, Thomas F. Westbrook, Don X. Nguyen, Qin Yan
Summary: Metastatic breast cancer is a leading cause of cancer-related deaths in women, with limited effective therapies available. Research has shown that reversible epigenetic mechanisms play a crucial role in tumor progression and metastasis. A recent study identified WDR5 as an actionable epigenetic regulator that is necessary for metastatic progression in triple-negative breast cancer models. Knockdown of WDR5 in breast cancer cells impairs their tumorigenic and metastatic capabilities, likely through increasing ribosomal gene expression and translation efficiency. Inhibition or degradation of WDR5 hampers cellular translation rate and clonogenic ability. Combining WDR5 targeting with mTOR inhibitors leads to potent suppression of translation and proliferation in breast cancer cells. These findings provide new therapeutic strategies for treating metastatic breast cancer.
Article
Biochemistry & Molecular Biology
Xufen Yu, Jun Wang, Weida Gong, Anqi Ma, Yudao Shen, Chengwei Zhang, Xijuan Liu, Ling Cai, Jing Liu, Gang Greg Wang, Jian Jin
Summary: This passage focuses on the noncanonical function of EZH2 in the development of multiple myeloma (MM), and proposes a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.
Article
Chemistry, Medicinal
Song Chen, Zhendong Chen, Lixue Lu, Yunpeng Zhao, Ronghui Zhou, Qiong Xie, Yongzhi Shu, Jun Lin, Xufen Yu, Yonghui Wang
Summary: Using PROTAC technology, researchers have discovered a highly potent BTK PROTAC compound that can effectively degrade hyperactivated B-cell receptor signaling pathway in various lymphoma cancers. Through structure-activity relationship studies, they have identified a novel CRBN-recruiting compound that can concentration-dependently induce BTK degradation and suppress cell growth with improved metabolic stability. This research provides a potential therapeutic approach for BTK-associated human cancers and diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biotechnology & Applied Microbiology
Jessica D. Umana, Sara R. Wasserman, Liujiang Song, Arushi A. Goel, Xufen Yu, Jian Jin, Nathaniel A. Hathaway
Summary: In this study, a chemically controllable AAV transgene expression technology was validated in vitro using chemical epigenetic modifiers (CEMs). This technology enhances AAV transgene expression by utilizing endogenous epigenetic machinery and can be reversibly controlled. By providing temporal gene expression control, this technology has the potential to increase the safety and efficiency of AAV-based research and therapies.
HUMAN GENE THERAPY
(2023)
Review
Chemistry, Multidisciplinary
Md Kabir, Xufen Yu, H. Umit Kaniskan, Jian Jin
Summary: Proteolysis-targeting chimeras (PROTACs) are small molecules that induce targeted degradation of proteins by forming ternary complexes with E3 ligases. They have the advantage of targeting both canonical and noncanonical functions of epigenetic targets, resulting in greater therapeutic efficacy. This review analyzes published PROTAC degraders of epigenetic writer, reader, and eraser proteins and discusses their mechanism of action and advantages in cancer treatment. Overall, pharmacological degradation of epigenetic targets has emerged as an effective strategy against cancer.
CHEMICAL SOCIETY REVIEWS
(2023)
Article
Chemistry, Medicinal
Xufen Yu, Jia Xu, Kaitlyn M. Cahuzac, Ling Xie, Yudao Shen, Xian Chen, Jing Liu, Ramon E. Parsons, Jian Jin
Summary: AKT is an important target for cancer therapeutics and significant advancements have been made in developing inhibitors. Recent research has discovered a novel AKT proteolysis targeting chimera (PROTAC) that shows potential in degrading AKT in cancer cells harboring KRAS/BRAF mutations.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Brandon Dale, Chris Anderson, Kwang-Su Park, H. Umit Kaniskan, Anqi Ma, Yudao Shen, Chengwei Zhang, Ling Xie, Xian Chen, Xufen Yu, Jian Jin
Summary: EZH2 overexpression is associated with poor prognosis in TNBC. A novel EZH2 PROTAC degrader, MS8815, has been discovered and shown to effectively suppress the growth of TNBC cells.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)