title: (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.
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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Ha-Soon
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Rucker
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 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 , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Albaugh
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: Chopiuk
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Francois
authors.initials: F
authors.lastname: Gessier
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 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 , 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 , 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 , 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 , 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 , 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 , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Che
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: McCormack
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Allen
authors.initials: A
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Auzon
authors.initials: A
authors.lastname: Steffy
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: AnneMarie
authors.initials: A
authors.lastname: Culazzo
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Celine
authors.initials: C
authors.lastname: Tompkins
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Van
authors.initials: V
authors.lastname: Phung
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 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 , 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 , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Apurva
authors.initials: A
authors.lastname: Chaudhary
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Mahavir
authors.initials: M
authors.lastname: Prashad
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 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 , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harris
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 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 , 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 , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Valentina
authors.initials: V
authors.lastname: Molteni
keywords: (R)-2-phenylpyrrolidine; GNF-8625; Neurotrophins; TRK; imidazopyridazines; tropomyosin receptor kinase