Abstract
Current cancer chemotherapy relies heavily on cytotoxic agents, such as the taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell division and divert the cell down a pathway of programmed cell death. These antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a protein required not only for mitosis but also for structural integrity and proper function of healthy, terminally differentiated cells. To avoid side effects attributed to this nonselective mechanism of action, new targets in the mitotic pathway that act only in dividing cells were sought and a leading candidate to emerge from these efforts was kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is expressed only during mitosis and controls the formation of a functional mitotic spindle. Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and thus has the potential to become a novel chemotherapeutic strategy with the potential for reduced toxicity. This article summarizes efforts carried out at Merck to discover potent, selective and water soluble KSP inhibitors that culminated in the discovery of MK-0731, the second KSP inhibitor to enter clinical trials. Of special focus in this article is how an HTS lead was optimized in apparently divergent directions, but these disparate leads converged in the design of compounds that overcame P-glycoprotein efflux and hERG channel activity, two issues that required considerable optimization within our program.
Keywords: Anti-mitotic, Eg5, hERG, mitotic arrest, P-glycoprotein (Pgp), QTc prolongation
Anti-Cancer Agents in Medicinal Chemistry
Title: Discovery of Allosteric Inhibitors of Kinesin Spindle Protein (KSP) for the Treatment of Taxane-Refractory Cancer: MK-0731 and Analogs
Volume: 10 Issue: 9
Author(s): Christopher D. Cox and Robert M. Garbaccio
Affiliation:
Keywords: Anti-mitotic, Eg5, hERG, mitotic arrest, P-glycoprotein (Pgp), QTc prolongation
Abstract: Current cancer chemotherapy relies heavily on cytotoxic agents, such as the taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell division and divert the cell down a pathway of programmed cell death. These antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a protein required not only for mitosis but also for structural integrity and proper function of healthy, terminally differentiated cells. To avoid side effects attributed to this nonselective mechanism of action, new targets in the mitotic pathway that act only in dividing cells were sought and a leading candidate to emerge from these efforts was kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is expressed only during mitosis and controls the formation of a functional mitotic spindle. Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and thus has the potential to become a novel chemotherapeutic strategy with the potential for reduced toxicity. This article summarizes efforts carried out at Merck to discover potent, selective and water soluble KSP inhibitors that culminated in the discovery of MK-0731, the second KSP inhibitor to enter clinical trials. Of special focus in this article is how an HTS lead was optimized in apparently divergent directions, but these disparate leads converged in the design of compounds that overcame P-glycoprotein efflux and hERG channel activity, two issues that required considerable optimization within our program.
Export Options
About this article
Cite this article as:
D. Cox Christopher and M. Garbaccio Robert, Discovery of Allosteric Inhibitors of Kinesin Spindle Protein (KSP) for the Treatment of Taxane-Refractory Cancer: MK-0731 and Analogs, Anti-Cancer Agents in Medicinal Chemistry 2010; 10 (9) . https://dx.doi.org/10.2174/187152010794479807
DOI https://dx.doi.org/10.2174/187152010794479807 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
Related Articles
-
The Role of cMet in Non-Small Cell Lung Cancer Resistant to EGFRInhibitors: Did We Really Find the Target?
Current Drug Targets Socioeconomic Consequences of Cervical Cancer: A Narrative Review
Current Women`s Health Reviews The p53 Pathway Encounters the MicroRNA World
Current Genomics Withdrawal Notice: EHNN-PKC: Integrated Neural Network-Point Kernel Classification for Lung Cancer Detection
Current Medical Imaging Nucleic Acid Aptamers: Clinical Applications and Promising New Horizons
Current Medicinal Chemistry Design, Synthesis and In vitro Biological Activity of Some New 1,3- thiazolidine-4-one Derivatives as Chemotherapeutic Agents using Virtual Screening Strategies
Current Computer-Aided Drug Design The Urokinase Receptor as a Potential Target in Cancer Therapy
Current Pharmaceutical Design Potential Therapeutic Targets for Steroid-Resistant Asthma
Current Drug Targets The Cellular and Molecular Basis of Health Benefits of Grape Seed Proanthocyanidin Extract
Current Pharmaceutical Biotechnology Therapeutic Exploitation of Apoptosis and Autophagy for Glioblastoma
Anti-Cancer Agents in Medicinal Chemistry Smoking and Weight
Current Respiratory Medicine Reviews A 30-years Review on Pharmacokinetics of Antibiotics: Is the Right Time for Pharmacogenetics?
Current Drug Metabolism Pharmacokinetics and In Vivo Fate of Drug Loaded Chitosan Nanoparticles<sup>++</sup>
Current Drug Metabolism Editorial (Thematic Issue: The Effects of Anticancer Agents on Cell Apoptosis and on the Expression of Cancer - Related Genes)
Anti-Cancer Agents in Medicinal Chemistry Novel Series of Coumarinyl Substituted-thiazolidin-2,4-dione Analogs as Anticancer Agents: Design, Synthesis, Spectral Studies and Cytotoxicity Evaluation
Anti-Cancer Agents in Medicinal Chemistry Monitoring T Cell Responses to Cancer Immunotherapy: Can We Now Identify Biomarkers Predicting Patients Who will be Responders
Current Cancer Therapy Reviews Leuckart Synthesis and Pharmacological Assessment of Novel Acetamide Derivatives
Anti-Cancer Agents in Medicinal Chemistry Targeting Mutant KRAS for Anticancer Therapy
Current Topics in Medicinal Chemistry Kinase Inhibitor Conjugates
Current Pharmaceutical Design Crystal Structure and Cytotoxic Activity of Co(II) Complex Containing N,N’-Tetra-(4-Antipyrylmethyl)-1,2-Diaminoethane (TAMEN) as Ligand
Medicinal Chemistry