The clinical development of new mitotic inhibitors that stabilize the microtubule

Mani, Sridhar; Macapinlac, M. P.; Goel, Sanjay; Verdier-Pinard, Dominik; Fojo, Tito; Rothenberg, Mace L.; Colevas, Dimitrios

doi:10.1097/01.cad.0000131681.21637.b2

Cited by 67 publications

(44 citation statements)

References 25 publications

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“…16 The discovery of numerous compounds from natural sources which display a wide structural diversity and are cytotoxic by perturbation of the dynamic instability of microtubules has attracted much attention within the last two decades. [17][18][19][20] Microtubules have, therefore, become an attractive pharmacological target for anticancer drug discovery. [17][18][19][20] Almost all antimitotic agents interact with the α/β-tubulin dimer, rather than microtubule-associated proteins (MAPs) or other proteins involved in microtubule functions.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20] Microtubules have, therefore, become an attractive pharmacological target for anticancer drug discovery. [17][18][19][20] Almost all antimitotic agents interact with the α/β-tubulin dimer, rather than microtubule-associated proteins (MAPs) or other proteins involved in microtubule functions. The Vinca alkaloids, exemplified by vinblastine (Chart 1) and vincristine (Chart 1), as well as the taxanes, such as paclitaxel (Chart 1) and the semisynthetic analogue docetaxel (Chart 1), are the most commonly used antimitotic agents in the clinical treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Jain

Zhang

Zhou

et al. 2008

Bioorganic & Medicinal Chemistry

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Tryprostatin A is a potent inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole N a -H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole N a -H or the indole C-2 position influenced the mechanism of action of these analogues. nalogues 68 (IC 50 = 10 μM) and 67 (IC 50 = 19 μM) were 7-fold and 3.5-fold more potent, respectively than 1 (IC 50 = 68 μM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC 50 = 11.9 μM), MCF7 (IC 50 = 17.0 μM) and PC3 (IC 50 = 11.1 μM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Jain

Zhang

Zhou

et al. 2008

Bioorganic & Medicinal Chemistry

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“…41 Two epothilones, ixabepilone and patupilone, in clinical studies, have shown significant activity in men with CRPC. [42][43][44][45] A phase II study conducted by the Southwest Oncology Group (SWOG) included 42 men with chemotherapy-naive CRPC who received ixabepilone (40 mg/m 2 ) every three weeks.…”

Section: Other Cytotoxic Agents Epothilonesmentioning

confidence: 99%

Update on options for treatment of metastatic castration-resistant prostate cancer

Vishnu

Tan²

2010

OTT

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“…Tasidotin has also been shown to have unique effects on microtubules (3). At low concentrations (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) Amol/L), tasidotin seems to induce a prolonged lag phase in microtubule assembly, which is followed by the standard rate of microtubule assembly. At higher concentrations (>50 Amol/L), tasidotin inhibits the extent of microtubule assembly and induces a long lag time, which is not a feature of other antimicrotubule agents.…”

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confidence: 99%

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

Mita

Hammond

Bonate³

et al. 2006

Clinical Cancer Research

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Purpose: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. Experimental Design: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m 2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. Results: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m 2 . At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non^small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11months. Conclusions: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m 2 . The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

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The clinical development of new mitotic inhibitors that stabilize the microtubule

Cited by 67 publications

References 25 publications

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Update on options for treatment of metastatic castration-resistant prostate cancer

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

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