Abstract
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.
Keywords: Cancer, apoptosis, Mcl-1, Bcl-2, Bcl-xL, BH3-mimetics, small molecule inhibitors.
Current Medicinal Chemistry
Title:Recent Advances in Cancer Drug Development: Targeting Induced Myeloid Cell Leukemia-1 (Mcl-1) Differentiation Protein
Volume: 24 Issue: 40
Author(s): Mohammad Abid*, Yogesh A. Sonawane, Jacob I. Contreras, Sandeep Rana and Amarnath Natarajan*
Affiliation:
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, 68198-6805,United States
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, 68198-6805,United States
Keywords: Cancer, apoptosis, Mcl-1, Bcl-2, Bcl-xL, BH3-mimetics, small molecule inhibitors.
Abstract: 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:
Abid Mohammad *, Sonawane A. Yogesh , Contreras I. Jacob , Rana Sandeep and Natarajan Amarnath *, 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
-
Radiosensitization of Prostate Cancer by Soy Isoflavones
Current Cancer Drug Targets Lipid Membrane; A Novel Target for Viral and Bacterial Pathogens
Current Drug Targets The Involvement of Heat Shock Proteins and Related Molecules in the Resistance to Therapies in Breast and Gynecologic Cancer
Current Cancer Therapy Reviews Tobacco, Inflammation, and Respiratory Tract Cancer
Current Pharmaceutical Design Imaging of Abdominal Aortic Aneurysm: The Present and the Future
Current Vascular Pharmacology Flavonoids in Cancer Prevention
Anti-Cancer Agents in Medicinal Chemistry C-11 Radiochemistry in Cancer Imaging Applications
Current Topics in Medicinal Chemistry Zoledronic Acid: Pleiotropic Anti-Tumor Mechanism and Therapeutic Outlook for Osteosarcoma
Current Drug Targets Induction of Abscopal Anti-Tumor Immunity and Immunogenic Tumor Cell Death by Ionizing Irradiation - Implications for Cancer Therapies
Current Medicinal Chemistry The Role of Mammalian Target of Rapamycin (mTOR) Inhibitors in the Treatment of Solid Tumors
Current Cancer Therapy Reviews Distribution and Characteristics of Intrathoracic Lymphadenopathy in TB/HIV Co-Infection
Infectious Disorders - Drug Targets Drug-Related Cardiotoxicity for the Treatment of Haematological Malignancies in Elderly
Current Pharmaceutical Design Irinotecan or Oxaliplatin: Which is the First Move for the Mate?
Current Medicinal Chemistry Review of PI3K/mTOR Inhibitors Entering Clinical Trials to Treat Triple Negative Breast Cancers
Recent Patents on Anti-Cancer Drug Discovery The Therapeutic Potential of 4-1BB (CD137) in Cancer
Current Cancer Drug Targets Sulfation of Phenylephrine by the Human Cytosolic Sulfotransferases
Drug Metabolism Letters Heteroaromatic Pim Kinase Inhibitors Containing a Pyrazole Moiety
Recent Patents on Anti-Cancer Drug Discovery Is Resistance Futile?
Current Drug Targets - Infectious Disorders The Potential of Modulating Small RNA Activity In Vivo
Mini-Reviews in Medicinal Chemistry Cytochrome P450-Activated Prodrugs: Targeted Drug Delivery
Current Medicinal Chemistry