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Denibulin

Description of Denibulin: Denibulin (MN-029) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. The results of preclinical study demonstrated that MN-029 could cause rapid vascular shutdown in solid tumors, dose-dependent secondary tumor cell killing, and effective enhancement of the antitumor effects of radiation and cisplatin chemotherapy.

Current developer: Medicinova, Inc./Angiogene Pharmaceuticals.

 MN-029 is a novel VDA that binds reversibly to the colchicine-binding site on tubulin and inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor endothelial cells (EC). Disruption of the tumor EC cytoskeleton ultimately leads to a temporary reduction in tumor blood flow.

MN-029 is a novel, small molecule VDA being developed for the treatment of solid tumors. Medicinova licensed MN-029 from Angiogene Pharmaceuticals, Ltd. Several preclinical pharmacology studies conducted by Angiogene Pharmaceuticals and us have assessed the mechanism of action and anti-tumor activity of MN-029 in vivo in rodent models of breast adenocarcinoma, colon carcinoma, lung carcinoma and KHT sarcoma. In these studies, MN-029 damaged poorly formed tumor blood vessels by weakening tumor blood vessel walls and causing leakage, clotting and eventual vascular shutdown within the tumor. These studies suggest that MN-029 acts quickly and is rapidly cleared from the body, which may reduce the potential for some adverse effects commonly associated with chemotherapy. Shutdown of tumor blood flow in tumor models was confirmed through the use of dynamic contrast-enhanced MRI.  See Medicinova's website.

1. Traynor, Anne M.; Gordon, Michael S.; Alberti, Dona; Mendelson, David S.; Munsey, Mark S.; Wilding, George; Gammans, Richard E.; Read, William L. A dose escalation, safety, and tolerability study of MN-029 in patients with advanced solid tumors. Investigational New Drugs (2010), 28(4), 509-515. CODEN: INNDDK ISSN:0167-6997. AN 2010:638288

2. Lee, Ray M.; Gewirtz, David A. Colchicine site inhibitors of microtubule integrity as vascular disrupting agents. Drug Development Research (2008), 69(6), 352-358. CODEN: DDREDK ISSN:0272-4391. CAN 150:229065 AN 2009:13930

3. Cai, Sui X. Small molecule vascular disrupting agents: potential new drugs for cancer treatment. Recent Patents on Anti-Cancer Drug Discovery (2007), 2(1), 79-101. CODEN: RPADDY ISSN:1574-8928. CAN 146:414035 AN 2007:141194

4. Shi, Wenyin; Siemann, Dietmar W. Preclinical studies of the novel vascular disrupting agent MN-029. Anticancer Research (2005), 25(6B), 3899-3904. CODEN: ANTRD4 ISSN:0250-7005. CAN 144:285716 AN 2005:1291495

5. Ryan, Anderson Joseph. Vascular damaging agents, such as ZD6126 for administration as an intravenous infusion for treatment of solid tumors. PCT Int. Appl. (2005), 26 pp. CODEN: PIXXD2 WO 2005110426 A1 20051124 CAN 143:483170 AN 2005:1242338

6. Traynor Anne M; Gordon Michael S; Alberti Dona; Mendelson David S; Munsey Mark S; Wilding George; Gammans Richard E; Read William L A dose escalation, safety, and tolerability study of MN-029 in patients with advanced solid tumors. Investigational new drugs (2010), 28(4), 509-15.

7. Cai Sui X Small molecule vascular disrupting agents: potential new drugs for cancer treatment. Recent patents on anti-cancer drug discovery (2007), 2(1), 79-101.

8. Shi Wenyin; Siemann Dietmar W Preclinical studies of the novel vascular disrupting agent MN-029. Anticancer research (2005), 25(6B), 3899-904.