Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models
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- 作者：Pam Albaugh ; Yi Fan ; Yuan Mi ; Fangxian Sun ; Francisco Adrian ; Nanxin Li ; Yong Jia ; Yelena Sarkisova ; Andreas Kreusch ; Tami Hood ; Min Lu ; Guoxun Liu ; Shenlin Huang ; Zuosheng Liu ; Jon Loren ; Tove Tuntland ; Donald S. Karanewsky ; H. Martin Seidel ; Valentina Molteni
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：February 9, 2012
- 年：2012
- 卷：3
- 期：2
- 页码：140-145
- 全文大小：280K
- 年卷期：v.3,no.2(February 9, 2012)
- ISSN：1948-5875
文摘
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.