(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: Ha-Soon Choi, Paul V Rucker, Zhicheng Wang, Yi Fan, Pamela Albaugh, Greg Chopiuk, Francois Gessier, Fangxian Sun, Francisco Adrian, Guoxun Liu, Tami Hood, Nanxin Li, Yong Jia, Jianwei Che, Susan McCormack, Allen Li, Jie Li, Auzon Steffy, AnneMarie Culazzo, Celine Tompkins, Van Phung, Andreas Kreusch, Min Lu, Bin Hu, Apurva Chaudhary, Mahavir Prashad, Tove Tuntland, Bo Liu, Jennifer Harris, H Martin Seidel, Jon Loren, Valentina Molteni
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 6 Issue 5 Pg. 562-7 (May 14 2015) ISSN: 1948-5875 [Print] United States
• PMID: 26005534 (Publication Type: Journal Article)