title: TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens.
abstract: Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G(2)-M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC(50) values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC(50) >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers.
authors.affiliation: Takeda Pharmaceutical Company Ltd., 26-1 Muraoka Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Hikichi_Yuichi@takeda.co.jp
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hikichi
authors.forename: Kohei
authors.initials: K
authors.lastname: Honda
authors.forename: Kouki
authors.initials: K
authors.lastname: Hikami
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyashita
authors.forename: Isao
authors.initials: I
authors.lastname: Kaieda
authors.forename: Saomi
authors.initials: S
authors.lastname: Murai
authors.forename: Noriko
authors.initials: N
authors.lastname: Uchiyama
authors.forename: Maki
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Sheldon
authors.initials: S
authors.lastname: Cao
authors.forename: Zhe
authors.initials: Z
authors.lastname: Nie
authors.forename: Lilly
authors.initials: L
authors.lastname: Zhang
authors.forename: Johnny
authors.initials: J
authors.lastname: Yang
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuida
authors.forename: Erik
authors.initials: E
authors.lastname: Kupperman
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D010129:4-Aminobenzoic Acid; D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D015507:Drugs, Investigational; D006657:Histones; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C573314:4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido(4,5-b)(1,4)diazepin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide