Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents

被引：54

作者：

DeSolms, SJ

Ciccarone, TM

MacTough, SC

Shaw, AW

Buser, CA

Ellis-Hutchings, M

Fernandes, C

Hamilton, KA

Huber, HE

Kohl, NE

Lobell, RB

Robinson, RG

Tsou, NN

Walsh, ES

Graham, SL ^{[1
]}

Beese, LS

Taylor, JS

机构：

[1] Merck Res Labs, Dept Med Chem, WP14-2,POB 4, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Mol Design & Diversity, Rahway, NJ 07065 USA

[4] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 14期

关键词：

D O I：

10.1021/jm020587n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.

引用

页码：2973 / 2984

页数：12

共 22 条

[1] Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase [J].

Anthony, NJ ;

Gomez, RP ;

Schaber, MD ;

Mosser, SD ;

Hamilton, KA ;

O'Neil, TJ ;

Koblan, KS ;

Graham, SL ;

Hartman, GD ;

Shah, D ;

Rands, E ;

Kohl, NE ;

Gibbs, JB ;

Oliff, AI .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (17) :3356-3368

[2] Inhibitors of protein prenylation 2000 [J].

Bell, IM .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2000, 10 (12) :1813-1831

[3]

BRADLEY G, 1980, EUR J MED CHEM, V15, P375

[4] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[5] Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines [J].

Cogan, DA ;

Liu, GC ;

Ellman, J .

TETRAHEDRON, 1999, 55 (29) :8883-8904

[6]

COX AD, 1997, BIOCHIM BIOPHYS ACTA, V1333, P51

[7] Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors [J].

Huber, HE ;

Robinson, RG ;

Watkins, A ;

Nahas, DD ;

Abrams, MT ;

Buser, CA ;

Lobell, RB ;

Patrick, D ;

Anthony, NJ ;

Dinsmore, CJ ;

Graham, SL ;

Hartman, GD ;

Lumma, WC ;

Williams, TM ;

Heimbrook, DC .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (27) :24457-24465

[8] Expedient synthesis of N-1-tritylimidazole-4-carboxaldehyde [J].

Jetter, MC ;

Boyd, RE ;

Reitz, AB .

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, 1996, 28 (06) :709-710

[9]

JONES TA, 1999, O VERSION 5 9 MANUAL

[10] Fluorobenzamidrazone thrombin inhibitors: Influence of fluorine on enhancing oral absorption [J].

Lee, K ;

Jung, WH ;

Hwang, SY ;

Lee, SH .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (17) :2483-2486

← 1 2 3 →