New Interfacial Microtubule Inhibitors of Marine Origin, PM050489/PM060184, with Potent Antitumor Activity and a Distinct Mechanism
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- 作者：Benet Pera ; Isabel Barasoain ; Areti Pantazopoulou ; Angeles Canales ; Ruth Matesanz ; Javier Rodriguez-Salarichs ; Luis F. Garc铆a-Fernandez ; Victoria Moneo ; Jes煤s Jim茅nez-Barbero ; Carlos M. Galmarini ; Carmen Cuevas ; Miguel A. Pe帽alva ; J. Fernando D铆az ; Jos茅 M. Andreu
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：September 20, 2013
- 年：2013
- 卷：8
- 期：9
- 页码：2084-2094
- 全文大小：576K
- 年卷期：v.8,no.9(September 20, 2013)
- ISSN：1554-8937
文摘
We have investigated the target and mechanism of action of a new family of cytotoxic small molecules of marine origin. PM050489 and its dechlorinated analogue PM060184 inhibit the growth of relevant cancer cell lines at subnanomolar concentrations. We found that they are highly potent microtubule inhibitors that impair mitosis with a distinct molecular mechanism. They bind with nanomolar affinity to unassembled 伪尾-tubulin dimers, and PM050489 binding is inhibited by known Vinca domain ligands. NMR TR-NOESY data indicated that a hydroxyl-containing analogue, PM060327, binds in an extended conformation, and STD results define its binding epitopes. Distinctly from vinblastine, these ligands only weakly induce tubulin self-association, in a manner more reminiscent of isohomohalichondrin B than of eribulin. PM050489, possibly acting like a hinge at the association interface between tubulin heterodimers, reshapes Mg2+-induced 42 S tubulin double rings into smaller 19 S single rings made of 7 卤 1 伪尾-tubulin dimers. PM060184-resistant mutants of Aspergillus nidulans map to 尾-tubulin Asn100, suggesting a new binding site different from that of vinblastine at the associating 尾-tubulin end. Inhibition of assembly dynamics by a few ligand molecules at the microtubule plus end would explain the antitumor activity of these compounds, of which PM060184 is undergoing clinical trials.