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The Discovery and Development of Eg5 Inhibitors for the Clinic

  • James A. D. GoodEmail author
  • Giacomo Berretta
  • Nahoum G. Anthony
  • Simon P. MackayEmail author
Chapter

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.

Keywords

Anti-mitotic Drug discovery Multiple myeloma Kinesins Eg5 

Abbreviations and Definitions

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

Kiapp

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

Notes

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, 34, 35, 36, 37, 38, 39].

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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Department of ChemistryUmeå UniversityUmeåSweden
  2. 2.Umeå Centre for Microbial ResearchUmeå UniversityUmeåSweden
  3. 3.Strathclyde Institute of Pharmacy and Biomedical SciencesUniversity of StrathclydeGlasgowUK

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