Synthesis and Biological Evaluation of Novel Analogues of the Pan Class I Phosphatidylinositol 3-Kinase (PI3K) Inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

被引:97
作者
Rewcastle, Gordon W. [1 ,2 ]
Gamage, Swarna A. [1 ]
Flanagan, Jack U. [1 ,2 ]
Frederick, Raphael [1 ,2 ]
Denny, William A. [1 ,2 ]
Baguley, Bruce C. [1 ,2 ]
Kestell, Philip [1 ]
Singh, Ripudaman [1 ]
Kendall, Jackie D. [1 ,2 ]
Marshall, Elaine S. [1 ]
Lill, Claire L. [1 ]
Lee, Woo-Jeong [3 ]
Kolekar, Sharada [3 ]
Buchanan, Christina M. [2 ,3 ]
Jamieson, Stephen M. F. [1 ,2 ]
Shepherd, Peter R. [2 ,3 ]
机构
[1] Univ Auckland, Auckland Canc Soc Res Ctr, Sch Med & Hlth Sci, Auckland 1142, New Zealand
[2] Univ Auckland, Maurice Wilkins Ctr Mol Biodiscovery, Auckland 1142, New Zealand
[3] Univ Auckland, Dept Mol Med & Pathol, Sch Med & Hlth Sci, Auckland 1142, New Zealand
关键词
PHOSPHOINOSITIDE; 3-KINASE; ANTITUMOR-ACTIVITY; PROTEIN-KINASE; BREAST-CANCER; MOUSE MODELS; TUMOR-GROWTH; PIK3CA GENE; POTENT; DISCOVERY; MECHANISMS;
D O I
10.1021/jm200688y
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A structure activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110 alpha, p110 beta, and p110 delta) and also displayed significant potency against two mutant forms of the p110 alpha isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Ragl(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd x 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
引用
收藏
页码:7105 / 7126
页数:22
相关论文
共 69 条
[1]   Cancer-specific mutations in PIK3CA are oncogenic in vivo [J].
Bader, AG ;
Kang, SY ;
Vogt, PK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (05) :1475-1479
[2]   RESISTANCE MECHANISMS DETERMINING THE IN-VITRO SENSITIVITY TO PACLITAXEL OF TUMOR-CELLS CULTURED FROM PATIENTS WITH OVARIAN-CANCER [J].
BAGULEY, BC ;
MARSHALL, ES ;
WHITTAKER, JR ;
DOTCHIN, MC ;
NIXON, J ;
MCCRYSTAL, MR ;
FINLAY, GJ ;
MATTHEWS, JHL ;
HOLDAWAY, KM ;
VANZIJL, P .
EUROPEAN JOURNAL OF CANCER, 1995, 31A (02) :230-237
[3]   INOTROPIC A RING SUBSTITUTED SULMAZOLE AND ISOMAZOLE ANALOGS [J].
BARRACLOUGH, P ;
BLACK, JW ;
CAMBRIDGE, D ;
COLLARD, D ;
FIRMIN, D ;
GERSKOWITCH, VP ;
GLEN, RC ;
GILES, H ;
HILL, AP ;
HULL, RAD ;
IYER, R ;
KING, WR ;
KNEEN, CO ;
LINDON, JC ;
NOBBS, MS ;
RANDALL, P ;
SHAH, GP ;
SMITH, S ;
VINE, SJ ;
WHITING, MV ;
WILLIAMS, JM .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (08) :2231-2239
[4]   Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110α and p110β catalytic subunits of class-Ia phosphoinositide 3-kinases [J].
Beeton, CA ;
Chance, EM ;
Foukas, LC ;
Shepherd, PR .
BIOCHEMICAL JOURNAL, 2000, 350 :353-359
[5]  
Berndt A, 2010, NAT CHEM BIOL, V6, P117, DOI [10.1038/nchembio.293, 10.1038/NCHEMBIO.293]
[6]   HETEROCYCLIC REARRANGEMENTS .V. REARRANGEMENT OF 4-ARYLAZO- AND 4-NITROSO-BENZOFUROXANS - NEW SYNTHESES FO BENZOTRIAZOLE AND BENZOFURAZAN RING SYSTEMS [J].
BOULTON, AJ ;
GHOSH, PB ;
KATRITZKY, AR .
JOURNAL OF THE CHEMICAL SOCIETY B-PHYSICAL ORGANIC, 1966, (10) :1004-+
[7]  
Butterworth S., 2008, PCT Int. Appl., Patent No. [WO 2008032027, 2008032027]
[8]  
BUTTERWORTH S, 2008, Patent No. 2008032064
[9]   Mutation of the PIK3CA gene in ovarian and breast cancer [J].
Campbell, IG ;
Russell, SE ;
Choong, DYH ;
Montgomery, KG ;
Ciavarella, ML ;
Hooi, CSF ;
Cristiano, BE ;
Pearson, RB ;
Phillips, WA .
CANCER RESEARCH, 2004, 64 (21) :7678-7681
[10]   Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis [J].
Camps, M ;
Rückle, T ;
Ji, H ;
Ardissone, V ;
Rintelen, F ;
Shaw, J ;
Ferrandi, C ;
Chabert, C ;
Gillieron, C ;
Françon, B ;
Martin, T ;
Gretener, D ;
Perrin, D ;
Leroy, D ;
Vitte, PA ;
Hirsch, E ;
Wymann, MP ;
Cirillo, R ;
Schwarz, MK ;
Rommel, C .
NATURE MEDICINE, 2005, 11 (09) :936-943