The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubuledestabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubuledestabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.drug mechanism | microtubule-targeting agents | X-ray crystallography
Ecteinascidins are marine natural products consisting of two or three linked tetrahydroisoquinoline subunits and an active carbinolamine functional group. Their potent antiproliferative activity against a variety of tumor cells makes them attractive candidates for development as anticancer agents. The lead compound, Yondelis (trabectedin, ET-743) is the first marine anticancer agent approved in the European Union for patients with soft tissue sarcoma (STS). Positive results of a large randomized Phase III clinical trial in ovarian cancer have recently been presented. The low amounts present in its natural source, the tunicate Ecteinascidia turbinata, made it necessary to develop efficient synthetic procedures. The original total synthesis is reviewed as well as a new semisythetic process from the readily available cynosafracin B, which has solved the supply problem.
An efficient new process is described for the synthesis of ecteinascidin ET-743 (1) and phthalascidin (2), starting from readily available cyanosafracin B (3).
Lamellarin D is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cell lines and is a potent inhibitor of topoisomerase I. However, lamellarin D maintains a marked cytotoxicity toward cell lines resistant to the reference topoisomerase I poison camptothecin. We therefore hypothesized that topoisomerase I is not the only cellular target for the drug. Using complementary cell-based assays, we provide evidence that lamellarin D acts on cancer cell mitochondria to induce apoptosis. Lamellarin D, unlike camptothecin, induces early disruption of the inner mitochondrial transmembrane potential (#y m ) in the P388 leukemia cell line. The functional alterations are largely prevented by cyclosporin A, an inhibitor of the mitochondrial permeability transition (MPT), but not by the inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone. #y m disruption is associated with mitochondrial swelling and cytochrome c leakage. Using a reliable real-time flow cytometric monitoring of #y m and swelling of mitochondria isolated from leukemia cells, we show that lamellarin D has a direct MPT-inducing effect. Furthermore, mitochondria are required in a cell-free system to mediate lamellarin D-induced nuclear apoptosis. The direct mitochondrial effect of lamellarin D accounts for the sensitivity of topoisomerase I-mutated P388CPT5 cells resistant to camptothecin. Interestingly, a tumor-active analogue of lamellarin D, designated PM031379, also exerts a direct proapoptotic action on mitochondria, with a more pronounced activity toward mitochondria of tumor cell lines compared with nontumor cell lines. Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells. (Cancer Res 2006; 66(6): 3177-87)
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