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Kinesin spindle protein inhibitors in cancer: a patent review (2008 - present)
1China Pharmaceutical University, Department of Medicinal Chemistry and Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Drug Design and Optimization , Nanjing 210009 , China.
Introduction:
Inhibition of kinesin spindle protein (KSP) has emerged as a novel and validated therapeutic strategy against cancers. A lot of new KSP inhibitors have been identified in recent years and some of them have entered clinical trials. This may provide more selections in future cancer therapy.
Areas Covered:
In the present review, the authors will describe the most recent classes of KSP inhibitors by reviewing about 96 literatures in which 24 patent applications were included from 2008 to now.
Expert Opinion:
Many new KSP inhibitors have been discovered that act either by binding in an allosteric site of KSP or by ATP competitive inhibition. There are several ATP non-competitive KSP inhibitors entering clinical investigation. Although they were both well tolerated and showed acceptable pharmacokinetic profiles, limited clinical response was always the problem. Mutation of the binding pocket was also a hindrance in the development of these allosteric inhibitors. The appearance of ATP competitive KSP inhibitors was considered to be able to overcome mutation-mediated resistance to the allosteric inhibitors, which could be a new approach for the development of novel KSP inhibitors.
Insights
New kinesin spindle protein (KSP) inhibitors offer promising cancer therapies. ATP-competitive KSP inhibitors may overcome resistance seen with allosteric inhibitors, representing a novel therapeutic approach.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Kinesin spindle protein (KSP) inhibition is a validated anti-cancer strategy.
- Numerous KSP inhibitors have been developed, with some progressing to clinical trials.
- This field offers expanding options for future cancer treatment.
Purpose of the Study:
- To review recent classes of KSP inhibitors.
- To analyze patent applications and literature from 2008 to the present.
- To discuss the therapeutic potential and challenges of KSP inhibitors.
Main Methods:
- Literature review of approximately 96 publications.
- Inclusion of 24 patent applications.
- Analysis of KSP inhibitor mechanisms and clinical data.
Main Results:
- Discovery of KSP inhibitors acting via allosteric or ATP-competitive mechanisms.
- Several ATP non-competitive inhibitors show good tolerability and pharmacokinetics.
- Limited clinical response and binding pocket mutations pose challenges for allosteric inhibitors.
Conclusions:
- ATP-competitive KSP inhibitors may overcome resistance associated with allosteric inhibitors.
- This class represents a novel approach for developing new KSP inhibitors.
- Further research into ATP-competitive KSP inhibitors is warranted for cancer therapy.
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