Antitumor 8-chlorobenzocycloheptapyridines: A new class of selective, nonpeptidic, nonsulfhydryl inhibitors of Ras farnesylation

被引：37

作者：

Mallams, AK ^{[1
]}

Njoroge, FG ^{[1
]}

Doll, RJ ^{[1
]}

Snow, ME ^{[1
]}

Kaminski, JJ ^{[1
]}

Rossman, RR ^{[1
]}

Vibulbhan, B ^{[1
]}

Bishop, WR ^{[1
]}

Kirschmeier, P ^{[1
]}

Liu, M ^{[1
]}

Bryant, MS ^{[1
]}

Alvarez, C ^{[1
]}

Carr, D ^{[1
]}

James, L ^{[1
]}

King, I ^{[1
]}

Li, Z ^{[1
]}

Lin, CC ^{[1
]}

Nardo, C ^{[1
]}

Petrin, J ^{[1
]}

Remiszewski, SW ^{[1
]}

Taveras, AG ^{[1
]}

Wang, S ^{[1
]}

Wong, J ^{[1
]}

Catino, J ^{[1
]}

Girijavallabhan, V ^{[1
]}

Ganguly, AK ^{[1
]}

机构：

[1] SCHERING PLOUGH CORP,RES INST,KENILWORTH,NJ 07033

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 1997年 / 5卷 / 01期

关键词：

D O I：

10.1016/S0968-0896(96)00205-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor. Copyright (C) 1997 Elsevier Science Ltd.

引用

页码：93 / 99

页数：7

共 17 条

[1] RAS GENES [J].

BARBACID, M .

ANNUAL REVIEW OF BIOCHEMISTRY, 1987, 56 :779-827

[2] Novel tricyclic inhibitors of farnesyl protein transferase - Biochemical characterization and inhibition of Ras modification in transfected Cos cells [J].

Bishop, WR ;

Bond, R ;

Petrin, J ;

Wang, L ;

Patton, R ;

Doll, R ;

Njoroge, G ;

Catino, J ;

Schwartz, J ;

Windsor, W ;

Syto, R ;

Schwartz, J ;

Carr, D ;

James, L ;

Kirschmeier, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (51) :30611-30618

[3] P21RAS IS MODIFIED BY A FARNESYL ISOPRENOID [J].

CASEY, PJ ;

SOLSKI, PA ;

DER, CJ ;

BUSS, JE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (21) :8323-8327

[4]

Graham S. L., 1995, EXPERT OPIN THER PAT, V5, P1269

[5] A BIOCHEMICAL FUNCTION FOR RAS - AT LAST [J].

HALL, A .

SCIENCE, 1994, 264 (5164) :1413-1414

[6]

KOBLAN KS, 1995, PROTEIN SCI, V4, P681

[7]

NAGASU T, 1995, CANCER RES, V55, P5310

[8]

PIWINSKI JJ, 1992, Patent No. 5089496

[9]

PIWINSKI JJ, 1989, Patent No. 4826853

[10]

PIWINSKI JJ, 1995, Patent No. 5422351

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