title: New interfacial microtubule inhibitors of marine origin, PM050489/PM060184, with potent antitumor activity and a distinct mechanism.
abstract: 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 αβ-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 Mg(2+)-induced 42 S tubulin double rings into smaller 19 S single rings made of 7 ± 1 αβ-tubulin dimers. PM060184-resistant mutants of Aspergillus nidulans map to β-tubulin Asn100, suggesting a new binding site different from that of vinblastine at the associating β-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.
authors.affiliation: Centro de Investigaciones Biológicas , CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Benet
authors.initials: B
authors.lastname: Pera
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: Areti
authors.initials: A
authors.lastname: Pantazopoulou
authors.forename: Angeles
authors.initials: A
authors.lastname: Canales
authors.forename: Ruth
authors.initials: R
authors.lastname: Matesanz
authors.forename: Javier
authors.initials: J
authors.lastname: Rodriguez-Salarichs
authors.forename: Luis F
authors.initials: LF
authors.lastname: García-Fernandez
authors.forename: Victoria
authors.initials: V
authors.lastname: Moneo
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuevas
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Peñalva
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: José M
authors.initials: JM
authors.lastname: Andreu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D061065:Polyketides / Q000737:chemistry / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C586199:PM050489; D061065:Polyketides; D011753:Pyrones; D014404:Tubulin; D050257:Tubulin Modulators; C586200:plocabulin