(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-IRK Inhibitors

被引：56

作者：

Choi, Ha-Soon ^{[1
]}

Rucker, Paul V. ^{[1
]}

Wang, Zhicheng ^{[1
]}

Fan, Yi ^{[1
]}

Albaugh, Pamela ^{[1
]}

Chopiuk, Greg ^{[1
]}

Gessier, Francois ^{[1
]}

Sun, Fangxian ^{[1
]}

Adrian, Francisco ^{[1
]}

Liu, Guoxun ^{[1
]}

Hood, Tami ^{[1
]}

Li, Nanxin ^{[1
]}

Jia, Yong ^{[1
]}

Che, Jianwei ^{[1
]}

McCormack, Susan ^{[1
]}

Li, Allen ^{[1
]}

Li, Jie ^{[1
]}

Steffy, Auzon ^{[1
]}

Culazzo, AnneMarie ^{[1
]}

Tompkins, Celine ^{[1
]}

Van Phung ^{[1
]}

Kreusch, Andreas ^{[1
]}

Lu, Min ^{[1
]}

Hu, Bin ^{[1
]}

Chaudhary, Apurva ^{[1
]}

Prashad, Mahavir ^{[1
]}

Tuntland, Tove ^{[1
]}

Liu, Bo ^{[1
]}

Harris, Jennifer ^{[1
]}

Seidel, H. Martin ^{[1
]}

Loren, Jon ^{[1
]}

Molteni, Valentina ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 05期

关键词：

Neurotrophins; tropomyosin receptor kinase; TRK; (R)-2-phenylpyrrolidine; imidazopyridazines; GNF-8625; NERVE GROWTH-FACTOR; PAPILLARY THYROID CARCINOMAS; PROTEIN-TYROSINE KINASE; HUMAN PANCREATIC-CANCER; PERINEURAL INVASION; NTRK1/NGF RECEPTOR; BREAST-CANCER; TRK ONCOGENES; EXPRESSION; REARRANGEMENTS;

D O I：

10.1021/acsmedchemlett.5b00050

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：562 / 567

页数：6

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