title: MPC-6827: a small-molecule inhibitor of microtubule formation that is not a substrate for multidrug resistance pumps.
abstract: A novel series of 4-arylaminoquinazolines were identified from a cell-based screening assay as potent apoptosis inducers. Through structure-activity relationship studies, MPC-6827 and its close structural analogue, MPI-0441138, were discovered as proapoptotic molecules and mitotic inhibitors with potencies at low nanomolar concentrations in multiple tumor cell lines. Photoaffinity and radiolabeled analogues of MPC-6827 were found to bind a 55-kDa protein, and this binding was competed by MPC-6827, paclitaxel, and colchicine, but not vinblastine. MPC-6827 effectively inhibited the polymerization of tubulin in vitro, competed with colchicine binding, and disrupted the formation of microtubules in a variety of tumor cell lines, which together showed the molecular target as tubulin. Treatment of MCF-7 breast carcinoma or Jurkat leukemia cells with MPC-6827 led to pronounced G2-M cell cycle arrest followed by apoptosis. Apoptosis, as determined by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay, was preceded by loss of mitochondrial membrane potential, cytochrome c translocation from mitochondria to nuclei, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. MPC-6827 was equipotent in an in vitro growth inhibition assay in several cancer cell lines regardless of the expression levels of the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. In B16-F1 allografts and in OVCAR-3, MIAPaCa-2, MCF-7, HT-29, MDA-MB-435, and MX-1 xenografts, statistically significant tumor growth inhibition was observed with MPC-6827. These studies show that MPC-6827 is a microtubule-disrupting agent with potent and broad-spectrum in vitro and in vivo cytotoxic activities and, therefore, MPC-6827 is a promising candidate for development as a novel therapeutic for multiple cancer types.
authors.affiliation: Epicept Corporation, San Diego, California, USA.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Vijay
authors.initials: V
authors.lastname: Baichwal
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
authors.forename: Bruce
authors.initials: B
authors.lastname: Roth
authors.forename: Ira
authors.initials: I
authors.lastname: Skvortsova
authors.forename: Sergej
authors.initials: S
authors.lastname: Skvortsov
authors.forename: Peter
authors.initials: P
authors.lastname: Lukas
authors.forename: Nicole M
authors.initials: NM
authors.lastname: English
authors.forename: Nilantha
authors.initials: N
authors.lastname: Sirisoma
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Azra
authors.initials: A
authors.lastname: Pervin
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: Robert O
authors.initials: RO
authors.lastname: Carlson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Pleiman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D011799:Quinazolines; D014404:Tubulin; D020169:Caspases; C522974:verubulin