Design, synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors

被引：10

作者：

Luo, Rongshuang ^{[1
,2
]}

Wang, Zhongyuan ^{[3
]}

Luo, Dali ^{[1
,2
]}

Qin, Yumei ^{[1
,2
]}

Zhao, Chunshen ^{[1
,2
]}

Yang, Di ^{[1
,2
]}

Lu, Tian ^{[4
]}

Zhou, Zhixu ^{[1
,2
,5
]}

Huang, Zhuyan ^{[1
,2
]}

机构：

[1] Guizhou Univ, Sch Pharmaceut Sci, Guiyang, Peoples R China

[2] Guizhou Engn Lab Synthet Drugs, Guiyang, Peoples R China

[3] Guizhou Prov Peoples Hosp, Dept Pharm, Guiyang, Peoples R China

[4] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China

[5] Guizhou Med Univ, Dept Dermatol, Affiliated Hosp, Guiyang, Peoples R China

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2021年 / 36卷 / 01期

关键词：

Triazoloquinazolinone derivatives; SHP2; inhibitors; A375 cell line; antitumor activity; ALLOSTERIC INHIBITION; TYROSINE; PHOSPHATASES; CANCER;

D O I：

10.1080/14756366.2021.1986491

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.

引用

页码：2170 / 2182

页数：13

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