摘要
背景:Bcl-2蛋白家族的抗凋亡成员在大多数癌症中上调,并且是潜在的治疗靶点。基于片段的设计导致了靶向Bcl-xL / Bcl-2的临床候选物的开发。尽管这些BclxL / Bcl-2抑制剂在临床前研究中显示出希望,但单独使用时观察到对几种Bcl-xL抑制剂的抗性。这归因于Bcl-2家族蛋白的另一个成员Mcl-1的过度表达。事实上,Mcl-1在许多癌症中高度扩增,表明它可能有助于恶性细胞生长和逃避凋亡。因此,对于癌症治疗的直接Mcl-1抑制剂的开发已经作出了重大的努力。 方法:经过对Mcl-1选择性抑制剂发展的同行评议文章的大量搜索,检索的文献按时间顺序安排和讨论在这篇评论文章。 结果:本文共纳入文章147篇,包括描述与Mcl-1选择性BH3模拟物具有改善的结合亲和力的钉合多肽的开发的文章,描述了各种研究小组基于片段和基于结构的小分子Mcl-1抑制剂设计的文章,以及详述使用天然产物及其衍生物作为潜在的Mcl-1抑制剂。 结论:靶向Mcl-1蛋白用于癌症药物发现的治疗潜力是巨大的。装订BH3肽以及开发小分子抑制剂如BH3模拟物是开发选择性Mcl-1抑制剂的可行策略。由于没有临床批准的候选人,扰乱这种蛋白质的生物功能的其他模式将有助于药物的发现努力。
关键词: 癌症,细胞凋亡,Mcl-1,Bcl-2,Bcl-xL,BH3-模拟物,小分子抑制剂。
Current Medicinal Chemistry
Title:Recent Advances in Cancer Drug Development: Targeting Induced Myeloid Cell Leukemia-1 (Mcl-1) Differentiation Protein
Volume: 24 Issue: 40
关键词: 癌症,细胞凋亡,Mcl-1,Bcl-2,Bcl-xL,BH3-模拟物,小分子抑制剂。
摘要: Background: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these BclxL/ Bcl-2 inhibitors showed promise in pre-clinical studies, resistance to several Bcl-xL inhibitors was observed, when used alone. This is attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins. Indeed, Mcl-1 is highly amplified in numerous cancers, suggesting that it may contribute to malignant cell growth and evasion of apoptosis. Therefore, significant efforts have been made toward the development of direct Mcl-1 inhibitors for cancer therapy.
Methods: Following an extensive search of peer-reviewed articles on the development of Mcl-1-selective inhibitors, the literature retrieved is chronologically arranged and discussed in this review article.
Results: We have included 147 articles in this review; including articles that describe the development of stapled peptides with improved binding affinity as Mcl-1-selective BH3 mimetics, those describing fragment-based and structure-based design of small molecule Mcl-1 inhibitors by various research groups, and those detailing the use of natural products and their derivatives as potential Mcl-1 inhibitors.
Conclusion: The therapeutic potential of targeting the Mcl-1 protein for cancer drug discovery is vast. Stapling BH3 peptides, as well as the development of small molecule inhibitors as BH3 mimetics, are viable strategies to develop selective Mcl-1 inhibitors. With no clinically approved candidate in hand, additional modes of perturbing the biological function of this protein will aid drug discovery efforts.
Export Options
About this article
Cite this article as:
Recent Advances in Cancer Drug Development: Targeting Induced Myeloid Cell Leukemia-1 (Mcl-1) Differentiation Protein, Current Medicinal Chemistry 2017; 24 (40) . https://dx.doi.org/10.2174/0929867324666170912092659
DOI https://dx.doi.org/10.2174/0929867324666170912092659 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Osteoprotegerin A Physiological and Pharmacological Inhibitor of Bone Resorption.
Current Pharmaceutical Design Novel Molecular Targets and Mechanisms Involved in the Invasion and Metastasis of Pancreatic Cancer
Clinical Cancer Drugs Acute Hypersensitivity Reactions to Chemotherapy Agents: An Overview
Inflammation & Allergy - Drug Targets (Discontinued) Targeted Cancer Therapy; Nanotechnology Approaches for Overcoming Drug Resistance
Current Medicinal Chemistry Advances on Cyclin-dependent Kinases (CDKs) as Novel Targets for Antiviral Drugs
Current Drug Targets - Infectious Disorders Clinical Development of Inhibitors of the Insulin-like Growth Factor Receptor in Oncology
Current Drug Targets Heparanase as a Target in Cancer Therapy
Current Cancer Drug Targets DNA Intercalators in Cancer Therapy: Organic and Inorganic Drugs and Their Spectroscopic Tools of Analysis
Mini-Reviews in Medicinal Chemistry Radiolabeled Probes Targeting Tyrosine-Kinase Receptors For Personalized Medicine
Current Pharmaceutical Design ABC Transporters in Multidrug Resistance and Pharmacokinetics, and Strategies for Drug Development
Current Pharmaceutical Design Modeling Anti-HIV Compounds: The Role of Analogue-Based Approaches
Current Computer-Aided Drug Design Molecular Targets in Gastrointestinal Stromal Tumors (GIST) Therapy
Current Cancer Drug Targets Optimizing Gene Silencing Strategies for Pancreatic Cancer
Current Cancer Therapy Reviews Design of New Drug Molecules to be Used in Reversing Multidrug Resistance in Cancer Cells
Current Cancer Drug Targets Viral Inhibition of Tumour Necrosis Factor-α (TNFα) and TNF-Receptor Induced Apoptosis and Inflammation
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents The Role of Co-Infections in Mother-to-Child Transmission of HIV
Current HIV Research Fetal Mesenchymal Stem Cells in Cancer Therapy
Current Stem Cell Research & Therapy Comparison of Physicochemical Properties of Generic Doxorubicin HCl Liposome Injection with the Reference Listed Drug
Anti-Cancer Agents in Medicinal Chemistry Stationary Wavelet Transform and AdaBoost with SVM Based Pathological Brain Detection in MRI Scanning
CNS & Neurological Disorders - Drug Targets Recent Imaging Advancements for Lung Metastases in Children with Sarcoma
Current Medical Imaging