Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy.
Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy.
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杂环稠合嘧啶作为针对秋水仙碱结合位点的新型微管蛋白聚合抑制剂：结构基础和抗肿瘤功效
DOI：
10.1021/acs.jmedchem.7b01858
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发表时间：
2018-02-22
影响因子：
7.3
通讯作者：
Miller DD
中科院分区：
文献类型：
--
作者：
Banerjee S;Arnst KE;Wang Y;Kumar G;Deng S;Yang L;Li GB;Yang J;White SW;Li W;Miller DD
我们报告了杂环稠合嘧啶类化合物作为微管蛋白聚合抑制剂的设计、合成和生物学评价，其靶向于秋水仙碱结合位点，具有显著改善的治疗指数。此外，我们首次报道了该支架中最佳化合物4a，4 b，6a和8b的高分辨率X射线晶体结构。这些结构不仅证实了它们与微管蛋白中秋水仙碱位点的直接结合，并揭示了它们详细的分子相互作用，而且与先前发表的结合模式形成了对比。化合物4a和6a在A375黑素瘤异种移植模型中显著抑制肿瘤生长，并伴随着细胞凋亡水平的升高和肿瘤血管系统的破坏。最后，我们证明了化合物4a在紫杉醇抗性PC-3/TxR前列腺癌异种移植模型中显著克服了临床相关的多药抗性。总的来说，这些研究提供了临床前和结构上的概念证明，以支持这种支架作为新一代微管蛋白抑制剂的持续发展。
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.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
Jesus Perez-Perez, Maria;Priego, Eva-Maria;Liekens, Sandra
通讯作者：
Liekens, Sandra
影响因子：
7.3
作者：
Greene, Thomas F.;Wang, Shu;Meegan, Mary J.
通讯作者：
Meegan, Mary J.
影响因子：
11.2
作者：
Kasibhatla, Shailaja;Baichwal, Vijay;Pleiman, Christopher M.
通讯作者：
Pleiman, Christopher M.
DOI：
10.1107/s0907444902016657
发表时间：
2002-11-01
影响因子：
2.2
作者：
Adams, PD;Grosse-Kunstleve, RW;Terwilliger, TC
通讯作者：
Terwilliger, TC