Epothilone D

"目录号: HY-15278

Cell Cycle/DNA DamageCytoskeleton-

Epothilone D 是一种有效的微管 (microtubule) 稳定剂。

Microtubule/Tubulin

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生物活性

Description

Epothilone D is a potentmicrotubulestabilizer.

IC50& Target

Microtubule/Tubulin[1]

In Vitro

Epothilone D (KOS-862) is a more potent microtubule stabilizer in vitro than epothilone A or B. In vitro, Epothilone D has shown potent cytotoxicity in a panel of human tumor cell lines, with similar potency to paclitaxel. Epothilone D also shows a definite advantage over paclitaxel in drug-resistant cell lines, and retained its cytotoxicity against a multidrug resistant cell line over-expressing P-glycoprotein[1]. Epothilone D (EpoD) is a microtubules (MTs)-stabilizing agent[2].

In Vivo

To evaluate whether Epothilone D (EpoD) improves MT and axonal function in PS19 mice, groups of 3-month old male PS19 mice received weekly i.p. injections of vehicle or Epothilone D (1 mg/kg or 3 mg/kg) for a total of 3 months. In addition, 3-month old non-Tg littermates received 3 mg/kg Epothilone D or vehicle. The 3 mg/kg Epothilone D dose corresponds to ~10-fold less than that used in a Phase II clinical study, which should minimize side-effects such as neutropenia that are observed with MT-stabilizing drugs in human subjects. PS19 and WT mice that receive Epothilone D show no signs of drug intolerance. Indeed, all drug-treated mice exhibited weight gain that is indistinguishable from vehicle-treated animals. Likewise, relative organ weights are similar in vehicle- and Epothilone D-treated mice. The motor performance of Epothilone D-treated mice, assessed using a standard rotarod test, is not significantly different from vehicle-treated cohorts. Finally, although there is minor group-to-group variability, there are no significant differences in white blood cell counts or neutrophil content between any of the treatment cohorts. Thus, the low doses of Epothilone D utilized in these studies appeared to be well tolerated[2].

Clinical Trial

NCT00030173

Bristol-Myers Squibb

Neoplasms

October 2001

Phase 1

NCT00077259

Memorial Sloan Kettering Cancer Center-National Cancer Institute (NCI)

Colorectal Cancer

October 2003

Phase 2

NCT00081107

Memorial Sloan Kettering Cancer Center-National Cancer Institute (NCI)

Lung Cancer

December 2003

Phase 2

NCT00337649

Hoffmann-La Roche

Breast Cancer

May 2004

Phase 2

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References

[1].Konner J, et al. Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma. Invest New Drugs. 2012 Dec;30(6):2294-302.

[2].Brunden KR, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci. 2010 Oct 13;30(41):13861-6.