Molteni, Valentina, Choi, Ha-Soon, Rucker, Paul, Wang, Zhicheng, Gessier, Francois, Liu, Guoxun, Hood, Tami, Li, Nanxin, Jia, Yong, Li, Jie, Steffy, Auzon, Pferdekamper, Annemarie, Kreusch, Andreas, Lu, Min, Chaudhary, Apurva, Prashad, Mahavir, Tuntland, Tove, Liu, Bo, Harris, Jennifer, Seidel, Martin and Tompkins, Celin (2015) (R)-2-Phenylpyrrolidine substituted imidazopyridazines: A new class of potent and selective pan-TRK inhibitors. ACS Medicinal Chemistry Letters, 6 (5). pp. 562-567. ISSN 1948-5875

Abstract

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

Item Type:	Article
Keywords:	(R)-2-phenylpyrrolidine GNF-8625 imidazopyridazines Neurotrophins TRK tropomyosin receptor kinase
Date Deposited:	18 Oct 2017 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/24702