The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC

被引：15

作者：

Chen, Lixue ^{[1
,2
]}

Chi, Fuyun ^{[3
]}

Wang, Tong ^{[1
,2
]}

Wang, Ning ^{[3
]}

Li, Wei ^{[1
,2
]}

Liu, Kexin ^{[3
]}

Shu, Xiaohong ^{[3
]}

Ma, Xiaodong ^{[3
]}

Xu, Youjun ^{[1
,2
]}

机构：

[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Liaoning, Peoples R China

[2] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R China

[3] Dalian Med Univ, Coll Pharm, Dalian 116044, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 23-24期

关键词：

NSCLC; EGFR T790M/L858R; Resistance; Inhibitors; GROWTH-FACTOR RECEPTOR; KINASE INHIBITORS; LUNG-CANCER; RESISTANCE; MUTATIONS; DISCOVERY; ERLOTINIB; THERAPY; ZD1839;

D O I：

10.1016/j.bmc.2018.11.009

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 series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFR(T790M/L858R) inhibitors among which 9c (IC50=0.5872 nM), 9d (IC50=2.213 nM), or 9h (IC50=12.57 nM) showed more potent anti-EGFR(T790M/L858R) activity compared with AZD-9291 (IC50=20.80 nM) and possessed high SI displaying 307.6, 56.5, or 12.5 for EGFR(T790M/L858R) over the wild-type respectively. 9h also showed pretty good activity against H 1975 cells with an IC50 of 1.664 mu M and exhibited low toxicity against the normal HBE cells (IC50 > 20 mu M). 9h had moderate selectivity for H 1975 over A 431 (SI=7.0) and the other selected cell lines. Morphological staining results further indicated that 9h could promote apoptosis. Hence, 9h was a promising compound for further investigation as a potential EGFR(T790M/L858R) inhibitor for the treatment of NSCLC.

引用

页码：6087 / 6095

页数：9

共 26 条

[1] Studies leading to the identification of ZD1839 (Iressa™):: An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer [J].

Barker, AJ ;

Gibson, KH ;

Grundy, W ;

Godfrey, AA ;

Barlow, JJ ;

Healy, MP ;

Woodburn, JR ;

Ashton, SE ;

Curry, BJ ;

Scarlett, L ;

Henthorn, L ;

Richards, L .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (14) :1911-1914

[2]

Bonomi P, 2003, EXPERT OPIN INV DRUG, V12, P1395, DOI 10.1517/eoid.12.8.1395.21769

[3] Drug therapy: EGFR antagonists in cancer treatment [J].

Ciardiello, Fortunato ;

Tortora, Giampaolo .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (11) :1160-1174

[4] EGF-ERBB signalling: towards the systems level [J].

Citri, Ami ;

Yarden, Yosef .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (07) :505-516

[5] United States Food and Drug Administration drug approval summary: Gefitinib (ZD1839; Iressa) tablets [J].

Cohen, MH ;

Williams, GA ;

Sridhara, R ;

Chen, G ;

McGuinn, WD ;

Morse, D ;

Abraham, S ;

Rahman, A ;

Liang, CY ;

Lostritto, R ;

Baird, A ;

Pazdur, R .

CLINICAL CANCER RESEARCH, 2004, 10 (04) :1212-1218

[6] FDA drug approval summary:: Erlotinib (Tarceva®) tablets [J].

Cohen, MH ;

Johnson, JR ;

Chen, YF ;

Sridhara, R ;

Pazdur, R .

ONCOLOGIST, 2005, 10 (07) :461-466

[7] Afatinib: First Global Approval [J].

Dungo, Rosselle T. ;

Keating, Gillian M. .

DRUGS, 2013, 73 (13) :1503-1515

[8] Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer [J].

Eck, Michael J. ;

Yun, Cai-Hong .

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2010, 1804 (03) :559-566

[9] Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor [J].

Ercan, D. ;

Zejnullahu, K. ;

Yonesaka, K. ;

Xiao, Y. ;

Capelletti, M. ;

Rogers, A. ;

Lifshits, E. ;

Brown, A. ;

Lee, C. ;

Christensen, J. G. ;

Kwiatkowski, D. J. ;

Engelman, J. A. ;

Jaenne, P. A. .

ONCOGENE, 2010, 29 (16) :2346-2356

[10] Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor [J].

Finlay, M. Raymond V. ;

Anderton, Mark ;

Ashton, Susan ;

Ballard, Peter ;

Bethel, Paul A. ;

Box, Matthew R. ;

Bradbury, Robert H. ;

Brown, Simon J. ;

Butterworth, Sam ;

Campbell, Andrew ;

Chorley, Christopher ;

Colclough, Nicola ;

Cross, Darren A. E. ;

Currie, Gordon S. ;

Grist, Matthew ;

Hassall, Lorraine ;

Hill, George B. ;

James, Daniel ;

James, Michael ;

Kemmitt, Paul ;

Klinowska, Teresa ;

Lamont, Gillian ;

Lamont, Scott G. ;

Martin, Nathaniel ;

McFarland, Heather L. ;

Mellor, Martine J. ;

Orme, Jonathon P. ;

Perkins, David ;

Perkins, Paula ;

Richmond, Graham ;

Smith, Peter ;

Ward, Richard A. ;

Waring, Michael J. ;

Whittaker, David ;

Wells, Stuart ;

Wrigley, Gail L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (20) :8249-8267

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