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The Discovery and Development of Eg5 Inhibitors for the Clinic

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Book cover Kinesins and Cancer

Abstract

The mitotic kinesin Eg5 (also known as kinesin spindle protein, KSP, Kif11, a member of the kinesin-5 family) represents an attractive oncology drug target in the ongoing development of anti-mitotic drugs that selectively block mitosis through disruption to the mitotic spindle. In this state-of-the-art review, we outline the progress that has been made in the development of Eg5 inhibitors for clinical use. We evaluate the preclinical development and attributes of key Eg5 inhibitors that have undergone clinical evaluation or extensive preclinical optimisation, and discuss the medicinal chemistry strategies utilised in their design to overcome the challenges encountered during lead optimisation. We critically analyse the progress that has been made towards delivering clinical benefits, and the wider implications this has in the utility of mitotic kinesin inhibitors as prospective oncology drugs.

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Abbreviations

AAG:

α-1-acid glycoprotein

AML:

Acute myeloid leukemia

Basal Eg5 inhibition:

Inhibition of the basal ATPase activity of Eg5

CBR:

Clinical benefit rate

CYP:

Cytochrome P450

DMPK:

Drug metabolism and pharmacokinetics

F:

Bioavailability

fu :

Fraction unbound

hERG:

Human ether-a-go-go-related gene

HHPQ:

Hexahydropyranoquinoline

HTS:

High-throughput screening

i.p.:

Intraperitoneal

K i app :

Estimated apparent K i value

MCL-1:

Antiapoptotic protein myeloid cell leukemia 1

MDR:

Multidrug resistance

MM:

Multiple myeloma

MT:

Microtubules

MT Eg5 inhibition:

Inhibition of the microtubule stimulated ATPase activity of Eg5

MTD:

Maximum tolerated dose

NCI:

National Cancer Institute

n.i.:

No inhibition

ORR:

Overall response rate

PK:

Pharmacokinetic

PgP:

P-glycoprotein

RRMM:

Relapsed/refractory multiple myeloma

SAR:

Structure activity relationship

STLC:

S-trityl L-cysteine

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Acknowledgments

We apologise to authors whose work we were unable to include due to limitations of space. We thank Prof. Frank Kozielski for helpful comments on the manuscript. We are grateful to Cancer Research UK for supporting the STLC programme and funding the postdoctoral positions of NGA and GB on the Small Molecule Drug Discovery Programme, in association with Prostate Cancer UK. JADG thanks the Umeå Centre for Microbial Research for funding his postdoctoral research at Umeå University.

Copyright Acknowledgements: Excerpts from this chapter appeared previously in the doctoral thesis of James A. D. Good [76]. The data appearing in Tables 2.1, 2.4 and 2.6 was adapted with permission from the cited references and is copyright American Chemical Society [15, 21, 25, 28, 58, 67]. The date appearing in Tables 2.2, 2.3 and 2.5 was adapted with permission from the cited references and is copyright Elsevier [26, 31, 33–39].

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Authors and Affiliations

  1. Department of Chemistry, Umeå University, 901 87, Umeå, Sweden

    James A. D. Good

  2. Umeå Centre for Microbial Research, Umeå University, 901 87, Umeå, Sweden

    James A. D. Good

  3. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK

    Giacomo Berretta, Nahoum G. Anthony & Simon P. Mackay

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  1. James A. D. Good
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  2. Giacomo Berretta
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  3. Nahoum G. Anthony
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  4. Simon P. Mackay
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Correspondence to James A. D. Good or Simon P. Mackay .

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Editors and Affiliations

  1. Chair, Department of Pharmaceutical and Biological Chemistry School of Pharmacy, University College London, London, United Kingdom

    Frank Kozielski, FSB

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Good, J.A.D., Berretta, G., Anthony, N.G., Mackay, S.P. (2015). The Discovery and Development of Eg5 Inhibitors for the Clinic. In: Kozielski, FSB, F. (eds) Kinesins and Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9732-0_2

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