Potent, Selective, and Orally Bioavailable Inhibitors of Mammalian Target of Rapamycin (mTOR) Kinase Based on a Quaternary Substituted Dihydrofuropyrimidine

被引：26

作者：

Cohen, Frederick ^{[1
]}

Bergeron, Philippe ^{[1
]}

Blackwood, Elizabeth ^{[2
]}

Bowman, Krista K. ^{[3
]}

Chen, Huifen ^{[1
]}

DiPasquale, Antonio G. ^{[7
]}

Epler, Jennifer A. ^{[2
]}

Koehler, Michael F. T. ^{[1
]}

Lau, Kevin ^{[1
]}

Lewis, Cristina ^{[4
]}

Liu, Lichuan ^{[5
]}

Ly, Cuong Q. ^{[1
]}

Malek, Shiva ^{[4
]}

Nonomiya, Jim ^{[4
]}

Ortwine, Daniel F. ^{[1
]}

Pei, Zhonghua ^{[1
]}

Robarge, Kirk D. ^{[1
]}

Sideris, Steve ^{[4
]}

Trinh, Lan ^{[4
]}

Truong, Tom ^{[2
]}

Wu, Jiansheng ^{[6
]}

Zhao, Xianrui ^{[1
]}

Lyssikatos, Joseph P. ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biochem Pharmacol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[7] Univ Calif Berkeley, Xray Crystallog Facil, Berkeley, CA 94720 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 09期

关键词：

D O I：

10.1021/jm200215y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K-i < 1.0 nM and were highly (>100x) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.

引用

页码：3426 / 3435

页数：10

共 19 条

[1] Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition
Breuleux, Madlaina
Klopfenstein, Matthieu
Stephan, Christine
Doughty, Cheryl A.
Barys, Louise
Maira, Saveur-Michel
Kwiatkowski, David
Lane, Heidi A.
[J]. MOLECULAR CANCER THERAPEUTICS, 2009, 8 (04) : 742 - 753
[2] Targeting the mTOR signaling network in cancer
Chiang, Gary G.
Abraham, Robert T.
[J]. TRENDS IN MOLECULAR MEDICINE, 2007, 13 (10) : 433 - 442
[3] MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist
Cruciani, G
Carosati, E
De Boeck, B
Ethirajulu, K
Mackie, C
Howe, T
Vianello, R
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (22) : 6970 - 6979
[4] DANEL K, 1995, SYNTHESIS-STUTTGART, P934
[5] A SYNTHESIS OF 2,2,4-TRIMETHYL-4-HYDROXYTETRAHYDROFURAN A PRODUCT OF PHOTOLYSIS OF 4-METHYL-4-METHOXY-2-PENTANONE
GIANTURCO, MA
FRIEDEL, P
[J]. CANADIAN JOURNAL OF CHEMISTRY-BACK YEAR, 1965, 43 (07): : 2121 - +
[6] Grünwald V, 2002, CANCER RES, V62, P6141
[7] The Pharmacology of mTOR Inhibition
Guertin, David A.
Sabatini, David M.
[J]. SCIENCE SIGNALING, 2009, 2 (67) : pe24
[8] Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies
Javle, Milind M.
Shroff, Rachna T.
Xiong, Henry
Varadhachary, Gauri A.
Fogelman, David
Reddy, Shrikanth A.
Davis, Darren
Zhang, Yujian
Wolff, Robert A.
Abbruzzese, James L.
[J]. BMC CANCER, 2010, 10
[9] King RobertaS., 2009, DRUG METABOLISM HDB, P17
[10] Liu Qingsong, 2009, Drug Discov Today Ther Strateg, V6, P47

← 1 2 →