MPC-6827: A Small-Molecule Inhibitor of Microtubule Formation That Is Not a Substrate for Multidrug Resistance Pumps

Kasibhatla, Shailaja; Baichwal, Vijay; Cai, Sui Xiong; Roth, Bruce L.; Skvortsova, Ira; Skvortsov, Sergej; Lukáš, Peter; English, Nicole M.; Sirisoma, Nilantha; Drewe, John; Pervin, Azra; Tseng, Ben; Carlson, Robert; Pleiman, Christopher M.

doi:10.1158/0008-5472.can-07-0127

Cited by 105 publications

(99 citation statements)

References 23 publications

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“…CA4P has progressed through to phase III clinical trials, and AVE8062 (Sanofi-Aventis) has been reported to be in phase III evaluation for advanced-stage soft tissue sarcoma after failure of anthracycline and ifosfamide chemotherapies (trial NCT00699517). Other compounds include OXi4503 (14), NPI-2358 (15), CYT-997 (16), MPC-6827 (17), and EPC2407 (18,19). These latter agents have completed phase I evaluation and are under evaluation in phase II trials.…”

Section: Discussionmentioning

confidence: 99%

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

Kremmidiotis

Leske

Lavranos

et al. 2010

Molecular Cancer Therapeutics

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Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals. Mol Cancer Ther; 9(6); 1562-73. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

Kremmidiotis

Leske

Lavranos

et al. 2010

Molecular Cancer Therapeutics

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“…In vitro, MPC-6827 is potent at low nanomolar concentrations in multiple cancer types, including pancreas, prostate, breast, colon, non-small cell lung, small cell lung, ovarian, and brain cancers, melanoma, and leukemia. In cell lines overexpressing multidrug resistance pumps, the activity of MPC-6827 is similar to that in nonresistant cell lines, suggesting that it should be active against multidrugresistant tumors (1,2). In vivo, MPC-6827 significantly inhibits the growth of various subcutaneously implanted tumor lines (1,2).…”

Section: Introductionmentioning

confidence: 99%

“…In cell lines overexpressing multidrug resistance pumps, the activity of MPC-6827 is similar to that in nonresistant cell lines, suggesting that it should be active against multidrugresistant tumors (1,2). In vivo, MPC-6827 significantly inhibits the growth of various subcutaneously implanted tumor lines (1,2).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…1) is a small-molecule microtubule-destabilizing agent that causes mitotic arrest and cell death (1). It exerts antitumor activity by binding to the same (or nearby) sites on b-tubulin as colchicine and by inhibiting microtubule assembly in a manner that is similar to that of colchicine and the vinca alkaloid drugs (1). In vitro, MPC-6827 is potent at low nanomolar concentrations in multiple cancer types, including pancreas, prostate, breast, colon, non-small cell lung, small cell lung, ovarian, and brain cancers, melanoma, and leukemia.…”

Section: Introductionmentioning

confidence: 99%

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Phase I Clinical Trial of MPC-6827 (Azixa), a Microtubule Destabilizing Agent, in Patients with Advanced Cancer

Tsimberidou

Akerley

Schabel

et al. 2010

Molecular Cancer Therapeutics

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MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on b-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1-to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m 2 , with subsequent increments of 0.6 mg/m 2 until the MTD was determined. A 3 þ 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1-10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m 2 (1/6 patients) and at 4.5 mg/m 2 (1/7 patients). The MTD was determined to be 3.3 mg/m 2 (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater.MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m 2 once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing.

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Effects of the Tumor‐Vasculature‐Disrupting Agent Verubulin and Two Heteroaryl Analogues on Cancer Cells, Endothelial Cells, and Blood Vessels

et al. 2014

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Two analogues of the discontinued tumor vascular-disrupting agent verubulin (Azixa®, MPC-6827, 1) featuring benzo-1,4-dioxan-6-yl (compound 5 a) and N-methylindol-5-yl (compound 10) residues instead of the para-anisyl group on the 4-(methylamino)-2-methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single-digit nanomolar IC50 values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (Ebind =-9.8 kcal mol(-1) ) than verubulin (Ebind =-8.3 kcal mol(-1) ), 10 suppressed the formation of vessel-like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular-disrupting effects that led to hemorrhages and extensive central necrosis in the tumor.

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MPC-6827: A Small-Molecule Inhibitor of Microtubule Formation That Is Not a Substrate for Multidrug Resistance Pumps

Abstract: A novel series of 4-arylaminoquinazolines were identified from a cell-based screening assay as potent apoptosis inducers.

Cited by 105 publications

References 23 publications

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

Phase I Clinical Trial of MPC-6827 (Azixa), a Microtubule Destabilizing Agent, in Patients with Advanced Cancer

Effects of the Tumor‐Vasculature‐Disrupting Agent Verubulin and Two Heteroaryl Analogues on Cancer Cells, Endothelial Cells, and Blood Vessels

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