Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFRL858R/T790M inhibitors

被引：4

作者：

Fu, Jianfang ^{[1
]}

Yu, Jie ^{[1
]}

Zhang, Xiang ^{[1
]}

Chang, Yaoyao ^{[1
]}

Fan, Hongze ^{[1
]}

Dong, Mengzhen ^{[1
]}

Li, Mengjia ^{[1
]}

Liu, Yue ^{[2
]}

Hu, Jinxing ^{[1
]}

机构：

[1] Weifang Med Univ, Sch Pharm, Weifang, Shandong, Peoples R China

[2] Weifang Med Univ, Sch Basic Med, Weifang, Shandong, Peoples R China

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2023年 / 38卷 / 01期

基金：

中国国家自然科学基金;

关键词：

NSCLC; EGFR mutations; EGFR(L858R/T790M); antitumor; derivatives; CELL LUNG-CANCER; KINASE INHIBITORS; EGFR MUTATIONS; RESISTANCE;

D O I：

10.1080/14756366.2023.2205605

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：

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFR(L858R/T790M) and more than 76-fold selectivity for EGFR(WT). Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 mu M. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFR(L858R/T790M) by cell migration assay and apoptosis assay.

引用

页数：17

共 50 条

[21] Synthesis of Some New Thieno[2,3-d]pyrimidine Derivatives
Abdelrazek, Fathy M.
Mohamed, Ashraf M.
ElSayed, Akram N.
AFINIDAD, 2008, 65 (536) : 322 - 326
[22] SYNTHESIS AND REACTIONS OF SOME THIENO[2,3-D]PYRIMIDINE DERIVATIVES
KHALIL, ZH
GEIES, AA
PHOSPHORUS SULFUR AND SILICON AND THE RELATED ELEMENTS, 1991, 60 (3-4): : 223 - 231
[23] SYNTHESIS OF THIENO[2,3-D]PYRIMIDINE DERIVATIVES AND THEIR ANTIFUNGAL ACTIVITIES
KONNO, S
TSUNODA, M
WATANABE, R
YAMANAKA, H
FUJITA, F
OHTSUKA, N
ASANO, S
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 1989, 109 (07): : 464 - 473
[24] New method of thieno[2,3-d]pyrimidine derivatives synthesis
Ryabova, OB
Evstratova, ML
Makarov, VA
Tafeenko, VA
Granik, VG
KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII, 2004, (10): : 1564 - 1571
[25] Synthesis and reactions of some pyrido[2,3-d] pyrimidine derivatives
Al-Issa, S. A.
ASIAN JOURNAL OF CHEMISTRY, 2006, 18 (03) : 2145 - 2150
[26] Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3-d] Pyrimidine Derivatives and Their Ribofuranosides
Bhargava, Sangeeta
Rajwanshi, Lokesh Kumar
JOURNAL OF HETEROCYCLIC CHEMISTRY, 2018, 55 (08) : 1874 - 1879
[27] Design, synthesis, and evaluation of the anticonvulsant and antidepressant activities of pyrido[2,3-d]pyrimidine derivatives
Hong-Jian Zhang
Shi-Ben Wang
Xiang Wen
Jin-Zi Li
Zhe-Shan Quan
Medicinal Chemistry Research, 2016, 25 : 1287 - 1298
[28] SYNTHESIS OF SOME PYRIDO[2,3-D]PYRIMIDINE AND PYRIDO[3,2-D]PYRIMIDINE DERIVATIVES
SOLODUCHO, J
ARCHIV DER PHARMAZIE, 1990, 323 (08) : 513 - 515
[29] SYNTHESIS AND BIOLOGICAL-ACTIVITY OF SOME PYRIDO[2,3-D]PYRIMIDINE DERIVATIVES
BYSTRYAKOVA, ID
BUROVA, OA
CHELYSHEVA, GM
ZHILINKOVA, SV
SMIRNOVA, NM
SAFONOVA, TS
KHIMIKO-FARMATSEVTICHESKII ZHURNAL, 1991, 25 (12): : 31 - 33
[30] SYNTHESIS OF NOVEL THIENO[2,3-D]PYRIMIDINE, THIENO[2,3-B]PYRIDINE AND THIAZOLO[3,2-A]THIENO[2,3-D]PYRIMIDINE DERIVATIVES AND THEIR EFFECT ON THE PRODUCTION OF MYCOTOXINS
ABDELRAZEK, FM
SALAH, AM
ELBAZZA, ZE
ARCHIV DER PHARMAZIE, 1992, 325 (05) : 301 - 305

← 1 2 3 4 5 →