Article
Pharmacology & Pharmacy
Haobin Li, Lingling Wang, Fei Cao, Dehua Yu, Jing Yang, Xuefei Yu, Jinyun Dong, Jiang-Jiang Qin, Xiaoqing Guan
Summary: The study reports the design and synthesis of a class of STAT3 degraders based on proteolysis-targeting chimeras (PROTACs). The SDL-1 compound achieved degradation of STAT3 protein in vitro and exhibited good anti-gastric cancer cell proliferation activity, as well as inhibiting invasion and metastasis.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Shipeng He, Junhui Ma, Yuxin Fang, Ying Liu, Shanchao Wu, Guoqiang Dong, Wei Wang, Chunquan Sheng
Summary: The novel homo-PROTAC strategy induces self-degradation of MDM2, showing efficient disruption of MDM2-P53 interaction in non-small cell lung cancer cells. In in vivo studies, the homo-PROTAC exhibits potent antitumor activity targeting A549 xenografts, demonstrating its potential as a safe therapy for cancer treatment.
ACTA PHARMACEUTICA SINICA B
(2021)
Review
Biochemistry & Molecular Biology
Wen Li, Reham M. Elhassan, Xuben Hou, Hao Fang
Summary: The PROTAC technology, based on the ubiquitin-proteasome system, has become a potential strategy for targeted cancer therapy. It has advantages over traditional small-molecule inhibitors in terms of pharmacodynamics, selectivity, and drug resistance. Several small molecule PROTACs are currently in Phase I clinical trial, showing promising advances in targeted anticancer research.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Xiao Cheng, Shiqi Hu, Ke Cheng
Summary: Proteolysis-targeting chimera (PROTAC) is an emerging technique for degrading disease-related proteins. This study demonstrates the feasibility of using microneedle patches to directly deliver PROTACs into tumors, overcoming the challenges of solubility and lack of organ targeting. The microneedle patches enable prolonged drug release and exhibit excellent efficacy in degrading disease-related proteins and reducing tumor size.
Review
Oncology
Deborah Chirnomas, Keith R. Hornberger, Craig M. Crews
Summary: Protein degraders are a novel therapeutic modality that selectively target disease-associated proteins for elimination. They have advantages over traditional small-molecule inhibitors and have shown promising activity as cancer therapies in clinical trials. More evidence is needed, but protein degraders represent a new class of drugs for cancer treatment.
NATURE REVIEWS CLINICAL ONCOLOGY
(2023)
Article
Chemistry, Medicinal
Robert B. Kargbo
Summary: The BCL-2 protein family members, such as BCL-2, BCL-XL, and MCL-1, have shown promise as therapeutic targets for cancer treatment, exemplified by the FDA approval of venetoclax in 2016. Scientists are actively working on designing analogs with improved pharmacokinetics and pharmacodynamics. This Patent Highlight presents PROTAC compounds that effectively and selectively degrade BCL-2, offering potential applications in cancer treatment, autoimmune disorders, and immune system diseases.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Chemistry, Medicinal
Chao Wang, Han Wang, Cangxin Zheng, Zhenming Liu, Xiaozuo Gao, Fengrong Xu, Yan Niu, Liangren Zhang, Ping Xu
Summary: MEK1/2 are key components of the ERK pathway involved in regulating cellular processes. Targeting MEK is important for cancer therapy, and PROTAC technology can potentially overcome resistance to MEK inhibitors by inducing MEK degradation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Wenqing Li, Jiabin Zhang, Li Guo, Qiantao Wang
Summary: This study explores the use of molecular dynamics simulation and molecular mechanics combined with the generalized Born and surface area continuum solvation (MM/GBSA) method to solve the three-body problem in PROTAC modeling. The results validate the accuracy of the approach and demonstrate the qualitative and quantitative importance of PROTAC-induced protein-protein interactions in its modeling.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Review
Oncology
Jian Huang, Biyun Lin, Benyi Li
Summary: Prostate cancer relies on androgen receptor (AR) and treatments mainly focus on suppressing AR activity or reducing androgen production. Current therapies for castration-resistant prostate cancer (CRPC) have limited effectiveness in part due to AR gene mutations or splicing variations leading to AR reactivation.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jian-Jia Liang, Hang Xie, Rui-Hua Yang, Ni Wang, Zi-Jun Zheng, Chen Zhou, Ya-Lei Wang, Zhi-Jia Wang, Hong-Min Liu, Li-Hong Shan, Yu Ke
Summary: In this study, novel PROTACs containing different linker phthalimide degrons were designed, synthesized, and evaluated for their AR degradation activity. Compound A16 showed the best AR binding affinity and degradation activity, while B10 exhibited effective internalization and visualization in LNCaP cells. Molecular docking of A16 with AR and the DDB1-CRBN E3 ubiquitin ligase complex provides guidance for designing new PROTAC degrons targeting AR in prostate cancer therapy. This research represents progress towards developing novel and improved AR PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Poornachandra Yedla, Ahmed O. Babalghith, Vindhya Vasini Andra, Riyaz Syed
Summary: Cancer treatments with targeted therapy, specifically Proteolysis-Targeting Chimeras (PROTACs), have gained significant attention for their unique mechanism of action and ability to target undruggable proteins. This review focuses on PROTACs in prostate cancer, highlighting their superiority over conventional inhibitors, and discussing the challenges and future prospects in this field. It also explores the underlying pathophysiology of prostate cancer and provides insights into the structural design and linker strategies for PROTAC molecules.
Article
Chemistry, Medicinal
Haruna Tsujimura, Miyako Naganuma, Nobumichi Ohoka, Takao Inoue, Mikihiko Naito, Genichiro Tsuji, Yosuke Demizu
Summary: Targeted protein degradation (TPD) using chimeric molecules like proteolysis-targeting chimeras (PROTACs) has been studied as a strategy to selectively degrade intracellular proteins by utilizing the ubiquitin-proteasome system (UPS). Nucleic acid aptamers have shown potential as ligands for targeting proteins for degradation. In this study, nucleic acid aptamers were linked to estrogen receptor alpha (ER alpha) and E3 ubiquitin ligase ligands to construct chimeric molecules that could degrade ER alpha via UPS. These findings demonstrate the development of novel aptamer-based PROTACs for targeting intracellular proteins.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Zunyuan Wang, Zhen Ma, Zhengrong Shen
Summary: ERα plays a key role in breast cancer and has been a target for endocrine therapy, but long-term treatment with AIs or SERMs may lead to drug resistance and increase the risk of uterine cancer. Therefore, novel anti-breast cancer drugs based on different mechanisms of action, especially through selective degradation of ER, have attracted significant attention.
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2021)
Article
Chemistry, Medicinal
Le Guo, Yaxian Zhou, Xueqing Nie, Zhongrui Zhang, Zhen Zhang, Chunrong Li, Taobo Wang, Weiping Tang
Summary: PROTAC is a commonly used technology for targeted protein degradation, and the Rapid-TAC platform enables rapid synthesis of PROTAC through traceless coupling reaction, saving time and facilitating screening of active protein degraders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Linrong Chen, Liuquan Han, Shujun Mao, Ping Xu, Xinxin Xu, Ruibo Zhao, Zhihua Wu, Kai Zhong, Guangliang Yu, Xiaolei Wang
Summary: A031 is a highly effective androgen receptor degrader that induces the degradation of AR protein in VCaP cell lines in a time-dependent manner with an IC50 value of less than 0.25 mM. It is 5 times less toxic than EZLA and shows significant inhibitory effects on tumor growth in zebrafish transplanted with human prostate cancer (VCaP), providing a promising candidate for developing novel drugs for prostate cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
