keyword
https://read.qxmd.com/read/38505849/zx703-a-small-molecule-degrader-of-gpx4-inducing-ferroptosis-in-human-cancer-cells
#21
JOURNAL ARTICLE
Mengdie Hu, Xiaomei Li, Lin Wang, Yanping Zhang, Yujie Sun, Hui Hua, Huina Liu, Ting Cai, Dongsheng Zhu, Qiuping Xiang
Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction of ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, and biological evaluation of endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with the aim of inducing ferroptosis in cancer cells. Our efforts led to the discovery of compound 5i (ZX703), which significantly degraded GPX4 through the ubiquitin-proteasome and the autophagy-lysosome pathways in a dose- and time-dependent manner...
March 14, 2024: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/38505842/discovery-and-characterization-of-active-cbp-ep300-degraders-targeting-the-hat-domain
#22
JOURNAL ARTICLE
Iván Cheng-Sánchez, Katherine A Gosselé, Leonardo Palaferri, Mariia S Kirillova, Cristina Nevado
Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that simultaneously bind an E3 ligase and a protein of interest, inducing degradation of the latter via the ubiquitin-proteasome system. Here we present the development of degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. Our PROTAC campaign focused on CPI-1612, a reported inhibitor of the histone acetyltransferase (HAT) domain of these two proteins...
March 14, 2024: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/38504115/protacable-is-an-integrative-computational-pipeline-of-3-d-modeling-and-deep-learning-to-automate-the-de-novo-design-of-protacs
#23
JOURNAL ARTICLE
Hazem Mslati, Francesco Gentile, Mohit Pandey, Fuqiang Ban, Artem Cherkasov
Proteolysis-targeting chimeras (PROTACs) that engage two biological targets at once are a promising technology in degrading clinically relevant protein targets. Since factors that influence the biological activities of PROTACs are more complex than those of a small molecule drug, we explored a combination of computational chemistry and deep learning strategies to forecast PROTAC activity and enable automated design. A new method named PROTACable was developed for the de novo design of PROTACs, which includes a robust 3-D modeling workflow to model PROTAC ternary complexes using a library of E3 ligase and linker and an SE(3)-equivariant graph transformer network to predict the activity of newly designed PROTACs...
March 19, 2024: Journal of Chemical Information and Modeling
https://read.qxmd.com/read/38501341/restraining-the-power-of-proteolysis-targeting-chimeras-in-the-cage-a-necessary-and-important-refinement-for-therapeutic-safety
#24
REVIEW
Renshuai Zhang, Songbo Xie, Jie Ran, Te Li
Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin-proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide-based, nucleic acid-based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch-activated PROTACs, offering precise targeting of previously "undruggable" proteins...
March 19, 2024: Journal of Cellular Physiology
https://read.qxmd.com/read/38498697/beyond-rule-of-five-and-protacs-in-modern-drug-discovery-polarity-reducers-chameleonicity-and-the-evolving-physicochemical-landscape
#25
JOURNAL ARTICLE
Edward Price, Manuel Weinheimer, Alexey Rivkin, Gary Jenkins, Marjoleen Nijsen, Philip B Cox, David DeGoey
Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against ∼1000 compounds with human absorption data and ∼10,000 AbbVie tool compounds (∼1000 proteolysis targeting chimeras or PROTACs, ∼7000 Ro5s, and ∼2000 bRo5s) revealed new patterns of physicochemical trends...
March 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38498082/design-synthesis-and-biological-evaluation-of-mnk-protacs
#26
JOURNAL ARTICLE
Xue Sun, Qingyun Wu, Hong Bu, Yifeng Pei, Dezhong Guan, Shi Guo, Jinpei Zhou, Huibin Zhang
Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) can regulate cellular mRNA translation by controlling the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), which plays an important role in tumor initiation, development, and metastasis. Although small-molecule MNK inhibitors have made significant breakthroughs in the treatment of various malignancies, their clinical application can be limited by drug resistance, target selectivity and other factors. The strategy of MNK-PROTACs which selectively degrades MNK kinases provides a new approach for developing small-molecule drugs for related diseases...
March 18, 2024: Molecular Diversity
https://read.qxmd.com/read/38494853/post-translational-modifications-in-diabetic-cardiomyopathy
#27
REVIEW
Zhi Li, Jie Chen, Hailong Huang, Qianru Zhan, Fengzhi Wang, Zihan Chen, Xinwei Lu, Guozhe Sun
The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria and targeted treatment approaches in clinical practice. Ongoing research is gradually unravelling the pathogenesis of diabetic cardiomyopathy, with a particular emphasis on investigating various post-translational modifications. These modifications dynamically regulate protein function in response to changes in the internal and external environment, and their disturbance of homeostasis holds significant relevance for the development of chronic ailments...
April 2024: Journal of Cellular and Molecular Medicine
https://read.qxmd.com/read/38490062/targeting-kelch-like-klhl-proteins-achievements-challenges-and-perspectives
#28
REVIEW
Yangguo Zhou, Qiong Zhang, Ziquan Zhao, Xiuqi Hu, Qidong You, Zhengyu Jiang
Kelch-like proteins (KLHLs) are a large family of BTB-containing proteins. KLHLs function as the substrate adaptor of Cullin 3-RING ligases (CRL3) to recognize substrates. KLHLs play pivotal roles in regulating various physiological and pathological processes by modulating the ubiquitination of their respective substrates. Mounting evidence indicates that mutations or abnormal expression of KLHLs are associated with various human diseases. Targeting KLHLs is a viable strategy for deciphering the KLHLs-related pathways and devising therapies for associated diseases...
February 29, 2024: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/38489998/discovery-of-lhf418-as-a-new-potent-sos1-protac-degrader
#29
JOURNAL ARTICLE
Huifan Li, Minxue Chai, Yihan Chen, Fengtao Zhou, Xiaomei Ren, Jian Xu, Jian Wang, Zhen Wang, Weixue Huang
Son of sevenless homolog 1 (SOS1) plays a pivotal role as a molecular switch in the conversion of GDP-bound inactive KRAS to its active GTP-bound form, making SOS1 a promising therapeutic target for KRAS-driven cancers. While the most advanced SOS1 inhibitor has processed to phase I clinical trial, the exploration of novel SOS1 targeting strategies with distinct modes of action remains required. By employing proteolysis targeting chimera (PROTAC) technology, we obtained a series of new SOS1 degraders. The representative compound LHF418 potently induced SOS1 degradation with a DC50 value of 209...
March 2, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38478885/structure-guided-design-and-optimization-of-covalent-vhl-targeted-sulfonyl-fluoride-protacs
#30
JOURNAL ARTICLE
Rishi R Shah, Elena De Vita, Preethi S Sathyamurthi, Daniel Conole, Xinyue Zhang, Elliot Fellows, Eleanor R Dickinson, Carlos M Fleites, Markus A Queisser, John D Harling, Edward W Tate
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site...
March 13, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38477974/discovery-of-cbpd-268-as-an-exceptionally-potent-and-orally-efficacious-cbp-p300-protac-degrader-capable-of-achieving-tumor-regression
#31
JOURNAL ARTICLE
Zhixiang Chen, Mi Wang, Dimin Wu, Longchuan Bai, Tianfeng Xu, Hoda Metwally, Yu Wang, Donna McEachern, Lijie Zhao, Ruiting Li, John Takyi-Williams, Meilin Wang, Lu Wang, Qiuxia Li, Bo Wen, Duxin Sun, Shaomeng Wang
CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and D max > 95%, leading to potent cell growth inhibition...
March 13, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38474412/proximity-induced-pharmacology-for-amyloid-related-diseases
#32
REVIEW
Andrea Bertran-Mostazo, Gabrielė Putriūtė, Irene Álvarez-Berbel, Maria Antònia Busquets, Carles Galdeano, Alba Espargaró, Raimon Sabate
Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer's disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer's disease...
March 4, 2024: Cells
https://read.qxmd.com/read/38474390/harmony-of-protein-tags-and-chimeric-molecules-empowers-targeted-protein-ubiquitination-and-beyond
#33
REVIEW
Aggie Lawer, Luke Schulz, Renata Sawyer, Xuyu Liu
Post-translational modifications (PTMs) are crucial mechanisms that underlie the intricacies of biological systems and disease mechanisms. This review focuses on the latest advancements in the design of heterobifunctional small molecules that hijack PTM machineries for target-specific modifications in living systems. A key innovation in this field is the development of proteolysis-targeting chimeras (PROTACs), which promote the ubiquitination of target proteins for proteasomal degradation. The past decade has seen several adaptations of the PROTAC concept to facilitate targeted (de)phosphorylation and acetylation...
February 28, 2024: Cells
https://read.qxmd.com/read/38469801/structurally-specific-z-dna-proteolysis-targeting-chimera-enables-targeted-degradation-of-adenosine-deaminase-acting-on-rna-1
#34
JOURNAL ARTICLE
Zhen Wang, Dingpeng Zhang, Xing Qiu, Hiroyuki Inuzuka, Yan Xiong, Jing Liu, Li Chen, He Chen, Ling Xie, H Ümit Kaniskan, Xian Chen, Jian Jin, Wenyi Wei
Given the prevalent advancements in DNA- and RNA-based PROTACs, there remains a significant need for the exploration and expansion of more specific DNA-based tools, thus broadening the scope and repertoire of DNA-based PROTACs. Unlike conventional A- or B-form DNA, Z-form DNA is a configuration that exclusively manifests itself under specific stress conditions and with specific target sequences, which can be recognized by specific reader proteins, such as ADAR1 or ZBP1, to exert downstream biological functions...
March 12, 2024: Journal of the American Chemical Society
https://read.qxmd.com/read/38466231/uncovering-protac-sensitivity-and-efficacy-by-multidimensional-proteome-profiling-a-case-for-stat3
#35
JOURNAL ARTICLE
Yuying Suo, Daohai Du, Chao Chen, Hongwen Zhu, Xiongjun Wang, Nixue Song, Dayun Lu, Yaxi Yang, Jiacheng Li, Jun Wang, Zhongyuan Luo, Bing Zhou, Cheng Luo, Hu Zhou
Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to a heterogeneous drug response, bringing about significant challenges in comprehending drug mechanisms. Our study applied data-independent acquisition-based mass spectrometry to multidimensional proteome profiling of PROTAC (DIA-MPP) to uncover the efficacy and sensitivity of the PROTAC compound. We profiled the signal transducer and activator of transcription 3 (STAT3) PROTAC degrader in six leukemia and lymphoma cell lines under multiple conditions, demonstrating the pharmacodynamic properties and downstream biological responses...
March 11, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/38464251/nsd2-is-a-requisite-subunit-of-the-ar-foxa1-neo-enhanceosome-in-promoting-prostate-tumorigenesis
#36
Abhijit Parolia, Sanjana Eyunni, Brijesh Kumar Verma, Eleanor Young, Lianchao Liu, James George, Shweta Aras, Chandan Kanta Das, Rahul Mannan, Reyaz Ur Rasool, Jie Luo, Sandra E Carson, Erick Mitchell-Velasquez, Yihan Liu, Lanbo Xiao, Prathibha R Gajjala, Mustapha Jaber, Tongchen He, Yuanyuan Qiao, Matthew Pang, Yuping Zhang, Mohammed Alhusayan, Xuhong Cao, Omid Tavana, Caiyun Hou, Zhen Wang, Ke Ding, Arul M Chinnaiyan, Irfan A Asangani
The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase...
March 1, 2024: bioRxiv
https://read.qxmd.com/read/38464204/protac-mediated-dual-degradation-of-bcl-xl-and-bcl-2-is-a-highly-effective-therapeutic-strategy-in-small-cell-lung-cancer
#37
Sajid Khan, Lin Cao, Janet Wiegand, Peiyi Zhang, Maria Zajac-Kaye, Frederic J Kaye, Guangrong Zheng, Daohong Zhou
BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation...
March 1, 2024: bioRxiv
https://read.qxmd.com/read/38464081/development-of-an-orally-bioavailable-mswi-snf-atpase-degrader-and-acquired-mechanisms-of-resistance-in-prostate-cancer
#38
Tongchen He, Caleb Cheng, Yuanyuan Qiao, Hanbyul Cho, Eleanor Young, Rahul Mannan, Somnath Mahapatra, Stephanie J Miner, Yang Zheng, NamHoon Kim, Victoria Z Zeng, Jasmine P Wisniewski, Siyu Hou, Bailey Jackson, Xuhong Cao, Fengyun Su, Rui Wang, Yu Chang, Bilash Kuila, Subhendu Mukherjee, Sandeep Dukare, Kiran B Aithal, Samiulla D S, Chandrasekhar Abbineni, Costas A Lyssiotis, Abhijit Parolia, Lanbo Xiao, Arul M Chinnaiyan
UNLABELLED: Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients...
March 2, 2024: bioRxiv
https://read.qxmd.com/read/38464025/discovery-of-the-first-in-class-g9a-glp-protac-degrader
#39
Julia Velez, Yulin Han, Hyerin Yim, Peiyi Yang, Zhijie Deng, Kwang-Su Park, Md Kabir, H Ümit Kaniskan, Yan Xiong, Jian Jin
Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader, 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases...
February 29, 2024: bioRxiv
https://read.qxmd.com/read/38456041/click-chemistry-in-the-development-of-protacs
#40
REVIEW
Ce Yang, Ravi Tripathi, Binghe Wang
Proteolysis-targeting chimeras or PROTACs are hetero-bifunctional molecules designed to mediate the disposal of a target protein via recruitment of the ubiquitination-proteasome degradation machinery. Because of the chimeric nature of such molecules, their synthesis requires a key step of "assembling" whether in the lab or in situ . Furthermore, targeted PROTACs often are hetero-trifunctional and require a second "assembling" step. Click chemistry has the unique advantages of tethering two or more molecular entities of choice under near physiological conditions and therefore has been applied to the development of PROTACs in various ways...
March 6, 2024: RSC chemical biology
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