A Potent, Metabolically Stable Tubulin Inhibitor Targets the Colchicine Binding Site and Overcomes Taxane Resistance.

Abstract

Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small-molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nmol/L. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation, and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.Significance: These findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation antitubulin drug for cancer therapy. Cancer Res; 78(1); 265-77. ©2017 AACR.

• Authors: Kinsie E Arnst, Yuxi Wang, Dong-Jin Hwang, Yi Xue, Terry Costello, David Hamilton, Qiang Chen, Jinliang Yang, Frank Park, James T Dalton, Duane D Miller, Wei Li
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 1 Pg. 265-277 (01 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29180476 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Bridged-Ring Compounds
• Imidazoles
• Indoles
• Pyridines
• Taxoids
• Tubulin
• Tubulin Modulators
• taxane
• Colchicine

Topics

• Animals
• Binding Sites
• Bridged-Ring Compounds (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Colchicine (metabolism)
• Crystallography, X-Ray
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Imidazoles (chemistry, pharmacology)
• Indoles (chemistry, pharmacology)
• Lung Neoplasms (drug therapy, pathology, secondary)
• Melanoma, Experimental (drug therapy, pathology)
• Mice, Inbred C57BL
• Mice, Nude
• Pyridines (chemistry, pharmacology)
• Taxoids (pharmacology)
• Tubulin (metabolism)
• Tubulin Modulators (adverse effects, chemistry, metabolism, pharmacology)
• Xenograft Model Antitumor Assays