title: Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo.
abstract: Abnormalities in the p16INK4a/ cyclin-dependent kinase (Cdk)4, 6/ Retinoblastoma (Rb) pathway frequently occur in various human cancers. Thus, Cdk4/6 is an attractive target for cancer therapy. Here we report the biological characterization of a 2-aminothiazole-derived Cdk4/6 selective inhibitor, named Compound A in vitro and in vivo. Compound A potently inhibits Cdk4 and Cdk6 with high selectivity (more than 57-fold) against other Cdks and 45 serine/threonine and tyrosine kinases. Compound A inhibits Rb protein (pRb) phosphorylation at Ser780, inhibits E2F-dependent transcription, and induces cell-cycle arrest at G1 in the T98G human glioma cell line. Among 82 human cells derived from various tissues, cell lines derived from hematological cancers (leukemia/lymphoma) tended to be more sensitive to Compound A in cell proliferation assay. Rb-negative cells tended to be insensitive to Compound A, as we had expected. In a nude rat xenograft model, Compound A inhibited pRb phosphorylation and bromodeoxyuridine (BrdU) incorporation in Eol-1 xenograft tumor at plasma concentration of 510 nM. Interestingly Compound A only moderately inhibited those pharmacodynamic and cell cycle parameters of normal crypt cells in small intestine even at 5 times higher plasma concentration. In F344 rats, Compound A did not cause immunosuppression even at 17 times higher plasma conc. These results suggest that Cdk4/6 selective inhibitors only moderately affects on the cell cycle of normal proliferating tissues and has a safer profile than pan-Cdk inhibitor in vivo.
authors.affiliation: Department of Oncology, Merck Research Laboratories, Tsukuba, Ibaraki, Japan. yrdyc661@yahoo.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirai
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Shimomura
authors.forename: Makiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Eguchi
authors.forename: Eri
authors.initials: E
authors.lastname: Taniguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fukasawa
authors.forename: Takumitsu
authors.initials: T
authors.lastname: Machida
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Arai
authors.forename: Koji
authors.initials: K
authors.lastname: Ichikawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hasako
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Haze
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kodera
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kawanishi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takahashi-Suziki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakatsuru
authors.forename: Hidehito
authors.initials: H
authors.lastname: Kotani
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Iwasawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050684:E2F Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D008297:Male; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D050684:E2F Transcription Factors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D013844:Thiazoles; C004483:2-aminothiazole; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6