Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

被引：84

作者：

Albaugh, Pam ^{[1
]}

Fan, Yi ^{[1
]}

Mi, Yuan ^{[1
]}

Sun, Fangxian ^{[1
]}

Adrian, Francisco ^{[1
]}

Li, Nanxin ^{[1
]}

Jia, Yong ^{[1
]}

Sarkisova, Yelena ^{[1
]}

Kreusch, Andreas ^{[1
]}

Hood, Tami ^{[1
]}

Lu, Min ^{[1
]}

Liu, Guoxun ^{[1
]}

Huang, Shenlin ^{[1
]}

Liu, Zuosheng ^{[1
]}

Loren, Jon ^{[1
]}

Tuntland, Tove ^{[1
]}

Karanewsky, Donald S. ^{[1
]}

Seidel, H. Martin ^{[1
]}

Molteni, Valentina ^{[1
]}

机构：

[1] Novartis Res Fdn GNF, Genom Inst, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 02期

关键词：

neurotrophins; NGF; tropomyosin receptor kinase; TRK; oxindole; GNF-5837; NERVE GROWTH-FACTOR; PAPILLARY THYROID CARCINOMAS; PROTEIN-TYROSINE KINASE; HUMAN PANCREATIC-CANCER; PERINEURAL INVASION; NTRK1/NGF RECEPTOR; EXPRESSION; REARRANGEMENTS; CELLS; ETV6-NTRK3;

D O I：

10.1021/ml200261d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.

引用

页码：140 / 145

页数：6

共 34 条

[1]

Anderws S. W., 2010, Patent No. [2010/033941-A1, 2010033941, 2010033941A1]

[2]

Beimfohr C, 1999, INT J CANCER, V80, P842, DOI 10.1002/(SICI)1097-0215(19990315)80:6<842::AID-IJC7>3.3.CO

[3]

2-Q

[4] TRK AND RET PROTOONCOGENE EXPRESSION IN HUMAN NEUROBLASTOMA SPECIMENS - HIGH-FREQUENCY OF TRK EXPRESSION IN NON-ADVANCED STAGES [J].

BORRELLO, MG ;

BONGARZONE, I ;

PIEROTTI, MA ;

LUKSCH, R ;

GASPARINI, M ;

COLLINI, P ;

PILOTTI, S ;

RIZZETTI, MG ;

MONDELLINI, P ;

DEBERNARDI, B ;

DIMARTINO, D ;

GARAVENTA, A ;

BRISIGOTTI, M ;

TONINI, GP .

INTERNATIONAL JOURNAL OF CANCER, 1993, 54 (04) :540-545

[5]

Bouhana K.S., Patent No. [WO11006074, 11006074]

[6]

Bounacer A, 2000, BRIT J CANCER, V82, P308

[7] A SEQUENCE-ANALYSIS OF THE GENOMIC REGIONS INVOLVED IN THE REARRANGEMENTS BETWEEN TPM3 AND NTRK1 GENES PRODUCING TRK ONCOGENES IN PAPILLARY THYROID CARCINOMAS [J].

BUTTI, MG ;

BONGARZONE, I ;

FERRARESI, G ;

MONDELLINI, P ;

BORRELLO, MG ;

PIEROTTI, MA .

GENOMICS, 1995, 28 (01) :15-24

[8] Small Molecule Recognition of c-Src via the lmatinib-Binding Conformation [J].

Dar, Arvin C. ;

Lopez, Michael S. ;

Shokat, Kevan M. .

CHEMISTRY & BIOLOGY, 2008, 15 (10) :1015-1022

[9]

Davidson B, 2003, CLIN CANCER RES, V9, P2248

[10] Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB [J].

Douma, S ;

van Laar, T ;

Zevenhoven, J ;

Meuwissen, R ;

van Garderen, E ;

Peeper, DS .

NATURE, 2004, 430 (7003) :1034-1040

← 1 2 3 4 →