Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site

Structural Basis and Antitumor Efficacy

Souvik Banerjee, Kinsie E. Arnst, Yuxi Wang, Gyanendra Kumar, Shanshan Deng, Lei Yang, Guo Bo Li, Jinliang Yang, Stephen W. White, Wei Li, Duane Miller

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors.

Original languageEnglish (US)
Pages (from-to)1704-1718
Number of pages15
JournalJournal of Medicinal Chemistry
Volume61
Issue number4
DOIs
StatePublished - Feb 22 2018

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Tubulin Modulators
Pyrimidines
Colchicine
Heterografts
Binding Sites
Multiple Drug Resistance
Tubulin
Paclitaxel
Melanoma
Neoplasms
Prostatic Neoplasms
X-Rays
Apoptosis
Growth
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site : Structural Basis and Antitumor Efficacy. / Banerjee, Souvik; Arnst, Kinsie E.; Wang, Yuxi; Kumar, Gyanendra; Deng, Shanshan; Yang, Lei; Li, Guo Bo; Yang, Jinliang; White, Stephen W.; Li, Wei; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 61, No. 4, 22.02.2018, p. 1704-1718.

Research output: Contribution to journalArticle

Banerjee, Souvik ; Arnst, Kinsie E. ; Wang, Yuxi ; Kumar, Gyanendra ; Deng, Shanshan ; Yang, Lei ; Li, Guo Bo ; Yang, Jinliang ; White, Stephen W. ; Li, Wei ; Miller, Duane. / Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site : Structural Basis and Antitumor Efficacy. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 4. pp. 1704-1718.
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