Annual review of PROTAC degraders as anticancer agents in 2022

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 267, С. 116166 - 116166

Опубликована: Янв. 25, 2024

Язык: Английский

---

HDAC-targeting epigenetic modulators for cancer immunotherapy

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 265, С. 116129 - 116129

Опубликована: Янв. 5, 2024

Язык: Английский

---

Pathological Role of HDAC8: Cancer and Beyond

Cells, Год журнала: 2022, Номер 11(19), С. 3161 - 3161

Опубликована: Окт. 9, 2022

Histone deacetylase 8 (HDAC8) is a class I HDAC that catalyzes the deacetylation of histone and non-histone proteins. As one best-characterized isoforms, numerous studies have identified interacting partners HDAC8 pertaining to diverse molecular mechanisms. Consequently, deregulation overexpression give rise diseases. especially involved in various aspects cancer progression, such as cell proliferation, metastasis, immune evasion, drug resistance. also associated with development non-cancer diseases Cornelia de Lange Syndrome (CdLS), infectious diseases, cardiovascular pulmonary myopathy. Therefore, an attractive therapeutic target selective inhibitors (HDAC8is) been developed. Here, we address pathological function other well illustrate several HDAC8is shown anti-cancer effects.

Язык: Английский

---

Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(24), С. 16860 - 16878

Опубликована: Дек. 6, 2022

In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve chemical knock-down of histone deacetylase 6 (HDAC6). Two series cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed rapid preparation two HDAC6 degrader mini libraries. The either based on an unselective vorinostat-like HDAC ligand or derived from selective inhibitor. Notably, both PROTAC demonstrated degradation in leukemia cell lines. best degraders each (denoted A6 and B4) capable degrading ternary complex formation ubiquitin–proteasome pathway, with DC50 values 3.5 19.4 nM, respectively. promising antiproliferative activity inducing apoptosis myeloid These findings highlight potential as effective pharmacological tools for targeted HDAC6.

Язык: Английский

---

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(2), С. 533 - 578

Опубликована: Сен. 12, 2023

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over past few decades, significant progress has been made development targeted epigenetic modulators (e.g., inhibitors). However, inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack subtype selectivity, drug resistance. As result, design new degraders) such as PROTACs, molecular glue, hydrophobic tagging (HyT) degraders garnered attention from both academia pharmaceutical industry, numerous discovered decade. In this review, we aim to provide an in-depth illustration degrading strategies (2017–2023) targeting proteins for cancer therapy, focusing on rational design, pharmacodynamics, pharmacokinetics, status, crystal structure information these degraders. Importantly, also deep insights into potential challenges corresponding remedies approach development. Overall, hope review will offer better mechanistic understanding serve useful guide emerging epigenetic-targeting

Язык: Английский

---

PROTACs: Novel tools for improving immunotherapy in cancer

Cancer Letters, Год журнала: 2023, Номер 560, С. 216128 - 216128

Опубликована: Март 16, 2023

Язык: Английский

---

Degraders in epigenetic therapy: PROTACs and beyond

Theranostics, Год журнала: 2024, Номер 14(4), С. 1464 - 1499

Опубликована: Янв. 1, 2024

Epigenetics refers to the reversible process through which changes in gene expression occur without changing nucleotide sequence of DNA. The is currently gaining prominence as a pivotal objective treatment cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from Food Drug Administration (FDA) for therapeutic intervention diverse diseases; many drawbacks, such limited applicability, toxicity, resistance. Since discovery first proteolysis-targeting chimeras (PROTACs) 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), TAG (dTAG), Trim-Away, specific non-genetic inhibitor apoptosis (IAP)-dependent eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight small-molecule degraders beyond PROTACs could achieve proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related methylation/demethylation related targets) via proteasomal or lysosomal pathways. present difficulties forthcoming prospects domain are also deliberated upon, may be valuable medicinal chemists when developing more potent, selective, drug-like clinical applications.

Язык: Английский

---

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(8), С. 6027 - 6043

Опубликована: Апрель 10, 2024

Targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has evolved into one of most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved treating a variety tumors, while development small-molecule PD-1/PD-L1 inhibitors lagged far behind, with only few entering clinical trials. In addition to and inhibitors, reducing expression levels PD-L1 attracted extensive research interest as another strategy target pathway. Herein, we analyze structures mechanisms molecules that reduce classify them degraders downregulators according whether they directly bind PD-L1. Moreover, discuss potential prospects developing PD-L1-targeting based on these molecules. It is hoped this perspective will provide profound insights discovery potent antitumor immunity drugs.

Язык: Английский

---

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(17), С. 10014 - 10014

Опубликована: Сен. 2, 2022

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on development selective HDAC8is. addition, polypharmacological approaches been explored achieve synergistic action multi-factorial diseases or enhance drug efficacy. this frame, proteolysis-targeting chimeras (PROTACs) might be regarded dual-targeting approach attaining proteasomal degradation. This review highlights most relevant advances relative validation providing snapshot current HDAC8is, focus polyfunctional modulators.

Язык: Английский

---

Discovery of highly potent HDAC8 PROTACs with anti-tumor activity

Bioorganic Chemistry, Год журнала: 2023, Номер 136, С. 106546 - 106546

Опубликована: Апрель 18, 2023

Various diseases are deeply associated with aberrations in HDAC8 functions. These can be assigned to either structural functions or catalytic of HDAC8. Therefore, development degradation inducers might more promising than inhibitors. We employed the proteolysis targeting chimera (PROTAC) strategy develop a selective and potent inducer CT-4 single-digit nanomolar DC50 values over 95% Dmax both triple-negative breast cancer MDA-MB-231 cells T-cell leukemia cells. Notably, demonstrated anti-migration activity limited anti-proliferative In contrast, effectively induced apototic cell death Jurkat cells, as assessed by caspase 3/7 assay flow cytometry. Our findings suggest that holds great potential for treatment HDAC8-related diseases.

Язык: Английский

---