The Discovery and Development of Eg5 Inhibitors for the Clinic

Good, James A. D.; Berretta, Giacomo; Anthony, Nahoum G.; Mackay, Simon P.

doi:10.1007/978-94-017-9732-0_2

“…Since these clinical candidates target the same binding site as that of monastrol and STLC, a common mode of inhibition is shared. The discovery and development of Eg5 inhibitors has been reviewed in detail elsewhere [41,67,68] and therefore this section will summarize the key features of the binding modes and the clinical outcomes to date.…”

Section: Eg5 Inhibitor Clinical Candidatesmentioning

confidence: 99%

Recent Findings and Future Directions for Interpolar Mitotic Kinesin Inhibitors in Cancer Therapy

Myers

¹

,

Collins

²

2016

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The kinesin class of microtubule-associated motor proteins present attractive anti-cancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms, and explore the implications for future anticancer drug development against these targets.

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“…The secondary amine proved to be critical for Eg5 inhibition, consistent with the reported structure activity relationships of ispinesib analogs. [48] Accordingly, 2 c, which maintains the secondary amine, proved to be a potent inhibitor (IC 50 = showed similar cytotoxicity in their cis-enriched forms. 5 b was relatively less cytotoxic compared with 5 a and 5 c. We decided to evaluate Azo-EMD (5 c) in further biological experiments because it showed the largest difference in IC 50 between cis and trans isomers.…”

Section: Methodsmentioning

confidence: 95%

Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

Trauner

¹

,

Impastato

²

,

Shemet

³

et al. 2022

Angewandte Chemie

1

0

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Eg5 is a kinesin motor protein that is responsible for bipolar spindle formation and plays a crucial role during mitosis. Loss of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death. Several cell‐permeable small molecules have been reported to inhibit Eg5 and some have been evaluated as anticancer agents. We now describe the design, synthesis, and biological evaluation of photoswitchable variants with five different pharmacophores. Our lead compound Azo‐EMD is a cell permeable azobenzene that inhibits Eg5 more potently in its light‐induced cis form. This activity decreased the velocity of Eg5 in single‐molecule assays, promoted formation of monopolar spindles, and led to mitotic arrest in a light dependent way.

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“…The secondary amine proved to be critical for Eg5 inhibition, consistent with the reported structure activity relationships of ispinesib analogs. [48] Accordingly, 2 c, which maintains the secondary amine, proved to be a potent inhibitor (IC 50 = Cell cycle analysis by DNA content showed that treatment with cis Azo-EMD (3 μM, 370 nm pulsed irradiation, 75 ms pulse every 15 s for 24 h) induced a strong shift towards the G2/M phases (Figure 3B). In comparison, cells treated with trans Azo-EMD in the dark (3 μM, 24 h) did not show a shift in cell cycle populations compared with cosolvent treated cells.…”

Section: Methodsmentioning

confidence: 98%

“…The secondary amine proved to be critical for Eg5 inhibition, consistent with the reported structure activity relationships of ispinesib analogs. [48] Accordingly, 2 c, which maintains the secondary amine, proved to be a potent inhibitor (IC 50 =…”

Section: Methodsmentioning

confidence: 99%

Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

Trauner

¹

,

Impastato

²

,

Shemet

³

et al. 2022

View full text Add to dashboard Cite

Eg5 is a kinesin motor protein that is responsible for bipolar spindle formation and plays a crucial role during mitosis. Loss of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death. Several cell‐permeable small molecules have been reported to inhibit Eg5 and some have been evaluated as anticancer agents. We now describe the design, synthesis, and biological evaluation of photoswitchable variants with five different pharmacophores. Our lead compound Azo‐EMD is a cell permeable azobenzene that inhibits Eg5 more potently in its light‐induced cis form. This activity decreased the velocity of Eg5 in single‐molecule assays, promoted formation of monopolar spindles, and led to mitotic arrest in a light dependent way.

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The Discovery and Development of Eg5 Inhibitors for the Clinic

Cited by 4 publications

References 64 publications

Recent Findings and Future Directions for Interpolar Mitotic Kinesin Inhibitors in Cancer Therapy

Recent Findings and Future Directions for Interpolar Mitotic Kinesin Inhibitors in Cancer Therapy

Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

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