Colchicine binding site agent DJ95 overcomes drug resistance and exhibits antitumor efficacy

Kinsie E. Arnst, Yuxi Wang, Zi Ning Lei, Dong Jin Hwang, Gyanendra Kumar, Dejian Ma, Deanna N. Parke, Qiang Chen, Jinliang Yang, Stephen W. White, Tiffany Seagroves, Zhe Sheng Chen, Duane Miller, Wei Li

Research output: Contribution to journalArticle

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Abstract

Interfering with microtubule dynamics is a well-established strategy in cancer treatment; however, many microtubule-targeting agents are associated with drug resistance and adverse effects. Substantial evidence points to ATP-binding cassette (ABC) transporters as critical players in the development of resistance. Herein, we demonstrate the efficacy of DJ95 (2-(1H-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine), a novel tubulin inhibitor, in a variety of cancer cell lines, including malignant melanomas, drug-selected resistant cell lines, specific ABC transporter-overexpressing cell lines, and the National Cancer Institute 60 cell line panel. DJ95 treatment inhibited cancer cell migration, caused morphologic changes to the microtubule network foundation, and severely disrupted mitotic spindle formation of mitotic cells. The high-resolution crystal structure of DJ95 in complex with tubulin protein and the detailed molecular interactions confirmed its direct binding to the colchicine site. In vitro pharmacological screening of DJ95 using SafetyScreen44 (Eurofins Cerep-Panlabs) revealed no significant off-target interactions, and pharmacokinetic analysis showed that DJ95 was maintained at therapeutically relevant plasma concentrations for up to 24 hours in mice. In an A375 xenograft model in nude mice, DJ95 inhibited tumor growth and disrupted tumor vasculature in xenograft tumors. These results demonstrate that DJ95 is potent against a variety of cell lines, demonstrated greater potency to ABC transporter-overexpressing cell lines than existing tubulin inhibitors, directly targets the colchicine binding domain, exhibits significant antitumor efficacy, and demonstrates vascular-disrupting properties. Collectively, these data suggest that DJ95 has great potential as a cancer therapeutic, particularly for multidrug resistance phenotypes, and warrants further development.

Original languageEnglish (US)
Pages (from-to)73-89
Number of pages17
JournalMolecular pharmacology
Volume96
Issue number1
DOIs
StatePublished - Jan 1 2019

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Colchicine
Drug Resistance
Binding Sites
Cell Line
ATP-Binding Cassette Transporters
Tubulin Modulators
Neoplasms
Microtubules
Heterografts
Spindle Apparatus
National Cancer Institute (U.S.)
Multiple Drug Resistance
Tubulin
Nude Mice
Cell Movement
Blood Vessels
Melanoma
Pharmacokinetics
Pharmacology
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Colchicine binding site agent DJ95 overcomes drug resistance and exhibits antitumor efficacy. / Arnst, Kinsie E.; Wang, Yuxi; Lei, Zi Ning; Hwang, Dong Jin; Kumar, Gyanendra; Ma, Dejian; Parke, Deanna N.; Chen, Qiang; Yang, Jinliang; White, Stephen W.; Seagroves, Tiffany; Chen, Zhe Sheng; Miller, Duane; Li, Wei.

In: Molecular pharmacology, Vol. 96, No. 1, 01.01.2019, p. 73-89.

Research output: Contribution to journalArticle

Arnst, KE, Wang, Y, Lei, ZN, Hwang, DJ, Kumar, G, Ma, D, Parke, DN, Chen, Q, Yang, J, White, SW, Seagroves, T, Chen, ZS, Miller, D & Li, W 2019, 'Colchicine binding site agent DJ95 overcomes drug resistance and exhibits antitumor efficacy', Molecular pharmacology, vol. 96, no. 1, pp. 73-89. https://doi.org/10.1124/mol.118.114801
Arnst, Kinsie E. ; Wang, Yuxi ; Lei, Zi Ning ; Hwang, Dong Jin ; Kumar, Gyanendra ; Ma, Dejian ; Parke, Deanna N. ; Chen, Qiang ; Yang, Jinliang ; White, Stephen W. ; Seagroves, Tiffany ; Chen, Zhe Sheng ; Miller, Duane ; Li, Wei. / Colchicine binding site agent DJ95 overcomes drug resistance and exhibits antitumor efficacy. In: Molecular pharmacology. 2019 ; Vol. 96, No. 1. pp. 73-89.
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