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 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
-
Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones
Current Medicinal Chemistry Radiolabeled Probes Targeting Tyrosine-Kinase Receptors For Personalized Medicine
Current Pharmaceutical Design Psoriasin, A Multifunctional Player in Different Diseases
Current Protein & Peptide Science Mitochondrial Permeability Transition as Target of Anticancer Drugs
Current Pharmaceutical Design Role of Transmembrane Domain/Transmembrane Domain Interfaces of PGlycoprotein (ABCB1) in Solute Transport. Convergent Information from Photoaffinity Labeling, Site Directed Mutagenesis and in Silico Importance Prediction
Current Medicinal Chemistry A Closer Look at “Social” Boundary Genes Reveals Knowledge to Gene Expression Profiles
Current Protein & Peptide Science Cyclic Peptide Containing Hydrophobic and Positively Charged Residues as a Drug Delivery System for Curcumin
Current Drug Delivery Specific Targeted Therapy: A New Tool for the Destruction of Cancer
Current Drug Therapy CXCR4 and CXCL12 Expression in Rectal Tumors of Stage IV Patients Before and After Local Radiotherapy and Systemic Neoadjuvant Treatment
Current Pharmaceutical Design Synthesis, Neuro-protection and Anti-cancer Activities of Simple Isatin Mannich and Schiff Bases
Letters in Drug Design & Discovery The Role of Mitochondria in Cancer Induction, Progression and Changes in Metabolism
Mini-Reviews in Medicinal Chemistry Dendritic Cells and their Receptors in Antitumor Immune Response
Current Molecular Medicine Anti-Proliferative Compounds for the Prevention of Restenosis: Anti-Restenotic Mechanisms of Paclitaxel Action
Current Pharmaceutical Design QSAR Studies of PTP1B Inhibitors: Recent Advances and Perspectives
Current Medicinal Chemistry Conjugation Approaches for Construction of Aptamer-Modified Nanoparticles for Application in Imaging
Current Topics in Medicinal Chemistry Synthesis and Bioactivity of (R)-Ricinoleic Acid Derivatives: A Review
Current Medicinal Chemistry The Potency of Refined Mouse Models: Implications for Clinical Trials
Current Cancer Therapy Reviews Atrial Remodeling and Novel Pharmacological Strategies for Antiarrhythmic Therapy in Atrial Fibrillation
Current Medicinal Chemistry Rationally Designed Anti-mitotic Agents with Pro-Apoptotic Activity
Current Pharmaceutical Design Biomolecules Linked to Transition Metal Complexes - New Chances for Chemotherapy
Current Medicinal Chemistry