Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors

被引：4

作者：

Mathison, Casey J. N. ^{[1
]}

Yang, Yang ^{[1
]}

Nelson, John ^{[1
]}

Huang, Zhihong ^{[1
]}

Jiang, Jiqing ^{[1
]}

Chianelli, Donatella ^{[1
]}

V. Rucker, Paul ^{[1
]}

Roland, Jason ^{[1
]}

Xie, Yun Feng ^{[1
]}

Epple, Robert ^{[1
]}

Bursulaya, Badry ^{[1
]}

Lee, Christian ^{[1
]}

Gao, Mu-Yun ^{[1
]}

Shaffer, Jennifer ^{[1
]}

Briones, Sergio ^{[1
]}

Sarkisova, Yelena ^{[1
]}

Galkin, Anna ^{[1
]}

Li, Lintong ^{[1
]}

Li, Nanxin ^{[1
]}

Li, Chun ^{[1
]}

Hua, Su ^{[1
]}

Kasibhatla, Shailaja ^{[1
]}

Kinyamu-Akunda, Jacqueline ^{[2
]}

Kikkawa, Rie ^{[2
]}

Molteni, Valentina ^{[1
]}

Tellew, John E. ^{[1
]}

机构：

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

[2] Novartis Inst Bio Med Res, E Hanover, NJ 07936 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2021年 / 12卷 / 12期

基金：

美国国家卫生研究院;

关键词：

RET; receptor tyrosine kinase; KDR; pyrrolo[2; 3-d]pyrimidine; Miles assay; KINASE INHIBITORS; POTENT; GENE;

D O I：

10.1021/acsmedchemlett.1c00450

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

引用

页码：1912 / 1919

页数：8

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[41] REGIOSELECTIVE SYNTHESIS OF PYRROLO[2,3-D]-PYRIMIDINE-2,4-DIONES AND "PYRIDO[2,3-D]-PYRIMIDINE-2,4-DIONES
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SAKAGUCHI, T
KAWASAKI, T
KITA, Y
[J]. HETEROCYCLES, 1975, 3 (02) : 183 - 186
[42] Identification and synthesis of substituted pyrrolo[2,3-d]pyrimidines as novel firefly luciferase inhibitors
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[43] Synthesis of novel pyrrolo[2,3-D]pyrimidines as inhibitors of thymidylate synthase and as antitumor agents
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Jain, H
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[44] A NOVEL AND FACILE SYNTHESIS OF PYRROLO[2,3-D]PYRIMIDINES
ITOH, T
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TOMII, Y
NISHIMURA, H
OGURA, H
MIZUNO, Y
KAWAHARA, N
SHIMAMORI, T
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KLUMPP, S
FREY, M
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SAUER, A
EGER, K
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