4-(1H-Indazol-5-yl)-6-phenylpyrimidin-2(1H)-one analogs as potent CDC7 inhibitors

被引：30

作者：

Shafer, Cynthia M. ^{[1
]}

Lindvall, Mika ^{[1
]}

Bellamacina, Cornelia ^{[1
]}

Gesner, Thomas G. ^{[1
]}

Yabannavar, Asha ^{[1
]}

Jia, Weiping ^{[1
]}

Lin, Song ^{[1
]}

Walter, Annette ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Div Oncol, Emeryville, CA 94608 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 16期

关键词：

phenol; pyrimidone; indazole; CDC7; pharmacophore model;

D O I：

10.1016/j.bmcl.2008.07.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 4-(4-hydroxyphenyl)-6-phenylpyrimidin-2(1H)-ones were identified by HTS as inhibitors of CDC7. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus on removing potential metabolic liabilities and improving cellular potency. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4482 / 4485

页数：4

共 15 条

[1] An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication [J].

Costanzo, V ;

Shechter, D ;

Lupardus, PJ ;

Cimprich, KA ;

Gottesman, M ;

Gautier, J .

MOLECULAR CELL, 2003, 11 (01) :203-213

[2] Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication [J].

Jiang, W ;

McDonald, D ;

Hope, TJ ;

Hunter, T .

EMBO JOURNAL, 1999, 18 (20) :5703-5713

[3] Inactivation of Cdc7 kinase in mouse ES cells results in S-phase arrest and p53-dependent cell death [J].

Kim, JM ;

Nakao, K ;

Nakamura, K ;

Saito, I ;

Katsuki, M ;

Arai, K ;

Masai, H .

EMBO JOURNAL, 2002, 21 (09) :2168-2179

[4] Phosphorylation of MCM4 by Cdc7 kinase facilitates its interaction with Cdc45 on the chromatin [J].

Masai, Hisao ;

Taniyama, Chika ;

Ogino, Keiko ;

Matsui, Etsuko ;

Kakusho, Naoko ;

Matsumoto, Seiji ;

Kim, Jung-Min ;

Ishii, Ai ;

Tanaka, Taku ;

Kobayashi, Toshiko ;

Tamai, Katsuyuki ;

Ohtani, Kiyoshi ;

Arai, Ken-ichi .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (51) :39249-39261

[5] CLONING AND CHARACTERIZATION OF THE HUMAN PIM-1 GENE - A PUTATIVE ONCOGENE RELATED TO THE PROTEIN-KINASES [J].

MEEKER, TC ;

NAGARAJAN, L ;

ARRUSHDI, A ;

CROCE, CM .

JOURNAL OF CELLULAR BIOCHEMISTRY, 1987, 35 (02) :105-112

[6] Drf1, a novel regulatory subunit for human Cdc7 kinase [J].

Montagnoli, A ;

Bosotti, R ;

Villa, F ;

Rialland, M ;

Brotherton, D ;

Mercurio, C ;

Berthelsen, J ;

Santocanale, C .

EMBO JOURNAL, 2002, 21 (12) :3171-3181

[7] Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases [J].

Montagnoli, A ;

Valsasina, B ;

Brotherton, D ;

Troiani, S ;

Rainoldi, S ;

Tenca, P ;

Molinari, A ;

Santocanale, C .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (15) :10281-10290

[8] Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells [J].

Montagnoli, A ;

Tenca, P ;

Sola, F ;

Carpani, D ;

Brotherton, D ;

Albanese, C ;

Santocanale, C .

CANCER RESEARCH, 2004, 64 (19) :7110-7116

[9] REACTION OF ALPHA, BETA-UNSATURATED KETONES WITH UREA - SYNTHESIS AND SPECTRAL PROPERTIES OF 2(1H)-PYRIMIDINONE DERIVATIVES [J].

SABRI, SS ;

HUSSEIN, AQ ;

ALHAJJAR, FH .

JOURNAL OF CHEMICAL AND ENGINEERING DATA, 1985, 30 (04) :512-514

[10] Cell cycle regulation of chromatin binding and nuclear localization of human Cdc7-ASK kinase complex [J].

Sato, N ;

Sato, M ;

Nakayama, M ;

Saitoh, R ;

Arai, K ;

Masai, H .

GENES TO CELLS, 2003, 8 (05) :451-463

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