Design, synthesis and biological evaluation of 3-(imidazo[1,2-a] pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors

被引：21

作者：

Cui, Shengyang ^{[1
,2
]}

Wang, Yongjin ^{[3
]}

Wang, Yuting ^{[3
]}

Tang, Xia ^{[3
]}

Ren, Xiaomei ^{[3
]}

Zhang, Lei ^{[4
]}

Xu, Yong ^{[1
,2
]}

Zhang, Zhang ^{[3
]}

Zhang, Zhi-Min ^{[3
]}

Lu, Xiaoyun ^{[3
]}

Ding, Ke ^{[3
]}

机构：

[1] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave, Guangzhou 510530, Guangdong, Peoples R China

[2] Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China

[3] Jinan Univ, Int Cooperat Lab Thadit Chinese Med Modernizat &, Guangzhou City Key Lab Precis Chem Drug Dev, Chinese Minist Educ MOE,Sch Pharm, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China

[4] Natl Facil Prot Sci Shanghai, Zhangjiang Lab, Shanghai 201210, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 179卷

基金：

中国国家自然科学基金;

关键词：

Tropomyosin receptor kinases(Trks); Inhibitor; Neuroblastoma; Cancer; ALK INHIBITOR; ACQUIRED-RESISTANCE; ANTITUMOR-ACTIVITY; CLINICAL-RESPONSE; ENTRECTINIB; IDENTIFICATION; ROS1; CARDIOTOXICITY; PROLIFERATION; ANGIOGENESIS;

D O I：

10.1016/j.ejmech.2019.06.064

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 90 suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 90 also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 90 may serve as a new lead compound for further anti-cancer drug discovery. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页码：470 / 482

页数：13

共 50 条

[1] The Phenix software for automated determination of macromolecular structures [J].

Adams, Paul D. ;

Afonine, Pavel V. ;

Bunkoczi, Gabor ;

Chen, Vincent B. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Hung, Li-Wei ;

Jain, Swati ;

Kapral, Gary J. ;

Kunstleve, Ralf W. Grosse ;

McCoy, Airlie J. ;

Moriarty, Nigel W. ;

Oeffner, Robert D. ;

Read, Randy J. ;

Richardson, David C. ;

Richardson, Jane S. ;

Terwilliger, Thomas C. ;

Zwart, Peter H. .

METHODS, 2011, 55 (01) :94-106

[2] Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications [J].

Ardini, Elena ;

Menichincheri, Maria ;

Banfi, Patrizia ;

Bosotti, Roberta ;

De Ponti, Cristina ;

Pulci, Romana ;

Ballinari, Dario ;

Ciomei, Marina ;

Texido, Gemma ;

Degrassi, Anna ;

Avanzi, Nilla ;

Amboldi, Nadia ;

Saccardo, Maria Beatrice ;

Casero, Daniele ;

Orsini, Paolo ;

Bandiera, Tiziano ;

Mologni, Luca ;

Anderson, David ;

Wei, Ge ;

Harris, Jason ;

Vernier, Jean-Michel ;

Li, Gang ;

Felder, Eduard ;

Donati, Daniele ;

Isacchi, Antonella ;

Pesenti, Enrico ;

Magnaghi, Paola ;

Galvani, Arturo .

MOLECULAR CANCER THERAPEUTICS, 2016, 15 (04) :628-639

[3] Combating autophagy is a strategy to increase cytotoxic effects of novel ALK inhibitor entrectinib in neuroblastoma cells [J].

Aveic, Sanja ;

Pantile, Marcella ;

Seydel, Anke ;

Esposito, Maria Rosaria ;

Zanon, Carlo ;

Li, Gary ;

Tonini, Gian Paolo .

ONCOTARGET, 2016, 7 (05) :5646-5663

[4] Genetic discoveries and treatment advances in neuroblastoma [J].

Bagatell, Rochelle ;

Cohn, Susan L. .

CURRENT OPINION IN PEDIATRICS, 2016, 28 (01) :19-25

[5] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016-Part II [J].

Bailey, Justin J. ;

Schirrmacher, Ralf ;

Farrell, Kristen ;

Bernard-Gauthier, Vadim .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2017, 27 (07) :831-849

[6] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016-Part I [J].

Bailey, Justin J. ;

Schirrmacher, Ralf ;

Farrell, Kristen ;

Bernard-Gauthier, Vadim .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2017, 27 (06) :733-751

[7] Identification of [18F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging [J].

Bernard-Gauthier, Vadim ;

Mossine, Andrew V. ;

Mahringer, Anne ;

Aliaga, Arturo ;

Bailey, Justin J. ;

Shao, Xia ;

Stauff, Jenelle ;

Arteaga, Janna ;

Sherman, Phillip ;

Grand'Maison, Marilyn ;

Rochon, Pierre-Luc ;

Waengler, Bjoern ;

Waengler, Carmen ;

Bartenstein, Peter ;

Kostikov, Alexey ;

Kaplan, David R. ;

Fricker, Gert ;

Rosa-Neto, Pedro ;

Scott, Peter J. H. ;

Schirrmacher, Ralf .

JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (04) :1737-1743

[8] A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human [J].

Bernard-Gauthier, Vadim ;

Bailey, Justin J. ;

Mossine, Andrew V. ;

Lindner, Simon ;

Vomacka, Lena ;

Aliaga, Arturo ;

Shao, Xia ;

Quesada, Carole A. ;

Sherman, Phillip ;

Mahringer, Anne ;

Kostikov, Alexey ;

Grand'Maison, Marilyn ;

Rosa-Neto, Pedro ;

Soucy, Jean-Paul ;

Thiel, Alexander ;

Kaplan, David R. ;

Fricker, Gert ;

Wangler, Bjoern ;

Bartenstein, Peter ;

Schirrmacher, Ralf ;

Scott, Peter J. H. .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (16) :6897-6910

[9] Trk Receptor Expression and Inhibition in Neuroblastomas [J].

Brodeur, Garrett M. ;

Minturn, Jane E. ;

Ho, Ruth ;

Simpson, Anisha M. ;

Iyer, Radhika ;

Varela, Carly R. ;

Light, Jennifer E. ;

Kolla, Venkatadri ;

Evans, Audrey E. .

CLINICAL CANCER RESEARCH, 2009, 15 (10) :3244-3250

[10] Research progress of neuroblastoma related gene variations [J].

Cao, Yanna ;

Jin, Yan ;

Yu, Jinpu ;

Wang, Jingfu ;

Yan, Jie ;

Zhao, Qiang .

ONCOTARGET, 2017, 8 (11) :18444-18455

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