title: Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Pam
authors.initials: P
authors.lastname: Albaugh
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Adrian
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Sarkisova
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreusch
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Tami
authors.initials: T
authors.lastname: Hood
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Guoxun
authors.initials: G
authors.lastname: Liu
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Shenlin
authors.initials: S
authors.lastname: Huang
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Zuosheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Loren
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Valentina
authors.initials: V
authors.lastname: Molteni
keywords: GNF-5837; NGF; TRK; neurotrophins; oxindole; tropomyosin receptor kinase