Article
Chemistry, Multidisciplinary
Guangyan Du, Jie Jiang, Qibiao Wu, Nathaniel J. Henning, Katherine A. Donovan, Hong Yue, Jianwei Che, Wenchao Lu, Eric S. Fischer, Nabeel Bardeesy, Tinghu Zhang, Nathanael S. Gray
Summary: DGY-09-192 is a potential prototype FGFR degrader with high selectivity, preferentially inducing degradation of FGFR1 and 2 while sparing FGFR3 and 4. In clinically relevant models, DGY-09-192 demonstrated the ability to degrade FGFR2 fusion proteins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
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
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
Biochemistry & Molecular Biology
Liguo Wang, Xuejing Shao, Tianbai Zhong, Yue Wu, Aixiao Xu, Xiuyun Sun, Hongying Gao, Yongbo Liu, Tianlong Lan, Yan Tong, Xue Tao, Wenxin Du, Wei Wang, Yingqian Chen, Ting Li, Xianbin Meng, Haiteng Deng, Bo Yang, Qiaojun He, Meidan Ying, Yu Rao
Summary: The study highlights the introduction of proteolysis-targeting chimeras (PROTACs) targeting of CDK2, which can promote differentiation of AML cells, providing a promising approach for treatment.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Peripheral Vascular Disease
Mohammad Shafid, Kumaravelu Jagavelu, Hina Iqbal, Pankaj Yadav, Debabrata Chanda, Neeraj Kumar Verma, Jimut Kanti Ghosh, Matthias Gaestel, Kashif Hanif
Summary: MK2 plays a significant role in pulmonary hypertension, and its inhibition may be a novel target for PH treatment. Inhibition of MK2 alleviated right ventricle pressure and hypertrophy in PH rats, improved cardiac function, reversed pulmonary vascular remodeling, and enhanced pulmonary vascular relaxation.
Article
Chemistry, Multidisciplinary
Xingui Liu, Alexia F. Kalogeropulou, Sofia Domingos, Nikolai Makukhin, Raja S. Nirujogi, Francois Singh, Natalia Shpiro, Anton Saalfrank, Esther Sammler, Ian G. Ganley, Rui Moreira, Dario R. Alessi, Alessio Ciulli
Summary: This study reports the development of LRRK2 proteolysis targeting chimeras (PROTACs) and the discovery of a degrader XL01126 as an alternative LRRK2-targeting strategy. XL01126 shows fast and potent degradation of LRRK2 in multiple cell lines, high cell permeability, and oral bioavailability, as well as the ability to penetrate the blood-brain barrier in mice.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(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
Cell Biology
Chang-Ning Fu, Jia-Wen Song, Zhi-Peng Song, Qian-Wen Wang, Wen-Wu Bai, Tao Guo, Peng Li, Chao Liu, Shuang-Xi Wang, Bo Dong
Summary: Statin-induced skeletal injury is mediated by the excessive expression of miR-1a, leading to decreased MAP3K1 gene expression and subsequent apoptosis of skeletal muscle cells.
Article
Chemistry, Medicinal
Pratik Pal, Dinesh Thummuri, Dongwen Lv, Xingui Liu, Peiyi Zhang, Wanyi Hu, Saikat K. Poddar, Nan Hua, Sajid Khan, Yaxia Yuan, Xuan Zhang, Daohong Zhou, Guangrong Zheng
Summary: This study reports a new series of BCLPROTACs, with the lead compound PZ703b showing high potency in inducing BCL-X-L degradation and inhibiting but not degrading BCL-2, demonstrating a unique hybrid dual-targeting mechanism in a PROTAC molecule.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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
Biochemistry & Molecular Biology
Qianqian Xu, Peiyu Zhang, Xiaoyan Han, Huwei Ren, Weiyue Yu, Wei Hao, Bowen Luo, Muhammad Imran Khan, Ni Chen
Summary: This study investigates the pivotal role of Nuclear factor-erythroid 2-related factor 2 (NRF2) in the activation of DNA damage repair in lung cancer cells after x-rays exposure. The study shows that NRF2 knockdown disrupts damaged DNA repair and homologous recombination, and NRF2 activation mediates DNA damage response via the MAPK pathway. These findings suggest that NRF2 plays a critical role in the development of radioresistance, which is of great significance for the development of radiotherapies.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
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
Agriculture, Dairy & Animal Science
Fuqing Huang, Kunling Teng, Yayong Liu, Tianwei Wang, Tianqi Xia, Fangfei Yun, Jin Zhong
Summary: Nisin Z has potential anti-inflammatory effects on mastitis by inhibiting the activation of the ERK1/2 and p38 MAPK signaling pathway and promoting the blood-milk barrier.
JOURNAL OF DAIRY SCIENCE
(2022)
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
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
Multidisciplinary Sciences
Sebastian Scheer, Suzanne Ackloo, Tiago S. Medina, Matthieu Schapira, Fengling Li, Jennifer A. Ward, Andrew M. Lewis, Jeffrey P. Northrop, Paul L. Richardson, H. Umit Kaniskan, Yudao Shen, Jing Liu, David Smil, David McLeod, Carlos A. Zepeda-Velazquez, Minkui Luo, Jian Jin, Dalia Barsyte-Lovejoy, Kilian V. M. Huber, Daniel D. De Carvalho, Masoud Vedadi, Colby Zaph, Peter J. Brown, Cheryl H. Arrowsmith
NATURE COMMUNICATIONS
(2019)
Article
Chemistry, Medicinal
Michael L. Martini, Jing Liu, Caroline Ray, Xufen Yu, Xi-Ping Huang, Aarti Urs, Nikhil Urs, John D. McCorvy, Marc G. Caron, Bryan L. Roth, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Yudao Shen, John D. McCorvy, Michael L. Martini, Ramona M. Rodriguiz, Vladimir M. Pogorelov, Karen M. Ward, William C. Wetsel, Jing Liu, Bryan L. Roth, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Yan Xiong, Holger Greschik, Catrine Johansson, Ludwig Seifert, Johannes Bacher, Kwang-su Park, Nicolas Babault, Michael Martini, Vincent Fagan, Fengling Li, Irene Chau, Thomas Christott, David Dilworth, Dalia Barsyte-Lovejoy, Masoud Vedadi, Cheryl H. Arrowsmith, Paul Brennan, Oleg Fedorov, Manfred Jung, Gillian Farnie, Jing Liu, Udo Oppermann, Roland Schuele, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Biochemistry & Molecular Biology
Michael L. Martini, Caroline Ray, Xufen Yu, Jing Liu, Vladimir M. Pogorelov, William C. Wetsel, Xi-Ping Huang, John D. McCorvy, Marc G. Caron, Jian Jin
ACS CHEMICAL NEUROSCIENCE
(2019)
Article
Chemistry, Medicinal
Xufen Yu, Xi-Ping Huang, Terry P. Kenakin, Samuel T. Slocum, Xin Chen, Michael L. Martini, Jing Liu, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Meng Cheng, Xufen Yu, Kaylene Lu, Ling Xie, Li Wang, Fanye Meng, Xiaoran Han, Xian Chen, Jing Liu, Yue Xiong, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Yudao Shen, Fengling Li, Magdalena M. Szewczyk, Levon Halabelian, Kwang-Su Park, Irene Chau, Aiping Dong, Hong Zeng, He Chen, Fanye Meng, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Peter J. Brown, Jing Liu, Masoud Vedadi, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Yudao Shen, Guozhen Gao, Xufen Yu, Huensuk Kim, Li Wang, Ling Xie, Megan Schwarz, Xian Chen, Ernesto Guccione, Jing Liu, Mark T. Bedford, Jian Jin
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Neurosciences
Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Jin Nakahara, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto
NATURE NEUROSCIENCE
(2020)
Article
Chemistry, Medicinal
Liqun Chen, Yanke Chen, Chunyan Zhang, Bingyang Jiao, Sheng Liang, Qiong Tan, Hongyu Chai, Weihua Yu, Yongzheng Qian, Hui Yang, Wuyi Yao, Jianguo Yu, Ying Luo, Michael Plewe, Jialiang Wang, Xiao-Ran Han, Jing Liu
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Shicheng Zhang, He Chen, Chengwei Zhang, Ying Yang, Petr Popov, Jing Liu, Brian E. Krumm, Can Cao, Kuglae Kim, Yan Xiong, Vsevolod Katritch, Brian K. Shoichet, Jian Jin, Jonathan F. Fay, Bryan L. Roth
Summary: This comprehensive study investigates the enigmatic serotonin receptor 5-HT5AR, including its pharmacological investigations and structures in different states. A highly selective and potent antagonist for 5-HT5AR was developed, and this study provides insights for structure-based drug discovery.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Can Cao, Hye Jin Kang, Isha Singh, He Chen, Chengwei Zhang, Wenlei Ye, Byron W. Hayes, Jing Liu, Ryan H. Gumpper, Brian J. Bender, Samuel T. Slocum, Brian E. Krumm, Katherine Lansu, John D. McCorvy, Wesley K. Kroeze, Justin G. English, Jeffrey F. DiBerto, Reid H. J. Olsen, Xi-Ping Huang, Shicheng Zhang, Yongfeng Liu, Kuglae Kim, Joel Karpiak, Lily Y. Jan, Soman N. Abraham, Jian Jin, Brian K. Shoichet, Jonathan F. Fay, Bryan L. Roth
Summary: Structural studies of MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide insights for developing therapeutic compounds for pain, itch, and mast cell-mediated hypersensitivity. These receptors are key mediators of itch and related mast cell-mediated hypersensitivity reactions.
Article
Chemistry, Medicinal
Karen J. Thompson, Elham Khajehali, Sophie J. Bradley, Jovana S. Navarrete, Xi Ping Huang, Samuel Slocum, Jian Jin, Jing Liu, Yan Xiong, Reid H. J. Olsen, Jeffrey F. Diberto, Kristen M. Boyt, Melanie M. Pina, Dipanwita Pati, Colin Molloy, Christoffer Bundgaard, Patrick M. Sexton, Thomas L. Kash, Michael J. Krashes, Arthur Christopoulos, Bryan L. Roth, Andrew B. Tobin
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2018)