Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents

El‐Nassan, Hala B.

doi:10.1016/j.ejmech.2013.01.031

Cited by 96 publications

(83 citation statements)

References 156 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ATP-competitive inhibitors of Eg5 like GSK1(Luo et al, 2007) that bind the α4-α6 pocket are specific for microtubule-bound protein but do not inhibit MM1S cells more potently than CD34 cells (Figure 6A) likely because MM cells contain higher levels of ATP. We are unaware of any inhibitor of Eg5 with the unique properties of BRD9876 thus far (although a wide variety of Eg5 inhibitors have been developed by pharmaceutical companies(El-Nassan, 2013)). BRD9876 is a tool compound and is not likely to be a drug candidate given its simple structure and lack of medicinal chemistry opportunities for optimization (Figure S3).…”

Section: Discussionmentioning

confidence: 99%

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

et al. 2015

View full text Add to dashboard Cite

Summary Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.

show abstract

Section: Discussionmentioning

confidence: 99%

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Eg5 has served as the most striking example of a "druggable" mitotic kinesin, with a large number of small molecule inhibitors that have been discovered and optimized [ 4 ]. Furthermore, Eg5, like a number of other mitotic kinesins, is up-regulated in a variety of cancers, consistent with one of the central requirements of the "oncogene addiction" hypothesis [ 27 -29 ].…”

Section: Phase I Trials Of Eg5 Inhibitorsmentioning

confidence: 96%

Clinical Trials of Mitotic Kinesin Inhibitors

Rosenfeld

2015

Kinesins and Cancer

View full text Add to dashboard Cite

“…It is the target for over twenty high-affinity, specific small molecule inhibitors that all bind to the same structural motif in the catalytic domain (13). Suppression of KIF11 function results in either prolonged mitotic arrest leading to cell death in mitosis or inappropriate progression through mitosis that is subsequently followed by cell death (14).…”

Section: Introductionmentioning

confidence: 99%

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

et al. 2015

View full text Add to dashboard Cite

The proliferative and invasive nature of malignant cancers drives lethality. In glioblastoma, these two processes are presumed mutually exclusive and hence termed “go or grow”. Here, we identified a molecular target that shuttles between these disparate cellular processes—the molecular motor KIF11. Inhibition of KIF11 with a highly specific small molecule inhibitor stopped the growth of both the more treatment resistant glioblastoma tumor initiating cells (TICs, or cancer stem cells) as well as non-TICs and impeded tumor initiation and self-renewal of the TIC population. Targeting KIF11 also hit the other arm of the “go or grow” cell fate decision by reducing glioma cell invasion. Administration of a KIF11 inhibitor to mice bearing orthotopic glioblastoma prolonged their survival. In its role as a shared molecular regulator of cell growth and motility across intratumoral heterogeneity, KIF11 is a compelling target for glioblastoma.

show abstract

Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents

Cited by 96 publications

References 156 publications

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

Clinical Trials of Mitotic Kinesin Inhibitors

The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma

Contact Info

Product

Resources

About