Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S

被引：55

作者：

Li, Qiannan ^{[1
]}

Zhang, Tao ^{[2
]}

Li, Shiliang ^{[1
]}

Tong, Linjiang ^{[2
]}

Li, Junyu ^{[1
]}

Su, Zhicheng ^{[1
]}

Feng, Fang ^{[2
]}

Sun, Deheng ^{[1
]}

Tong, Yi ^{[1
]}

Wang, Xia ^{[1
]}

Zhao, Zhenjiang ^{[1
]}

Zhu, Lili ^{[1
]}

Ding, Jian ^{[2
]}

Li, Honglin ^{[1
]}

Xie, Hua ^{[2
]}

Xu, Yufang ^{[1
]}

机构：

[1] East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 06期

基金：

中国国家自然科学基金;

关键词：

EGFR; mutant; inhibitor; C797S; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; MUTATIONS; GEFITINIB; AZD9291;

D O I：

10.1021/acsmedchemlett.8b00564

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR(L858R/T790M/C797S). One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFR(L8S8R/T790M/C797S) with an IC50 value of 2.2 nM. Cell proliferation assays showed that 25g effectively and selectively inhibited the growth of EGFR(L858R/T790M/C797S)-dependent cells. This series of compounds, which occupy both the ATP binding site and the allosteric site of the EGFR kinase, may serve as a basis for the development of fourth-generation EGFR inhibitors for L858R/T790M/C797S mutants.

引用

页码：869 / 873

页数：9

共 22 条

[1]

[Anonymous], MOD PATHOL

[2] Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer [J].

Chen, Lingfeng ;

Fu, Weitao ;

Zheng, Lulu ;

Liu, Zhiguo ;

Liang, Guang .

JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (10) :4290-4300

[3] 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

[4] Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models [J].

Eberlein, Catherine A. ;

Stetson, Daniel ;

Markovets, Aleksandra A. ;

Al-Kadhimi, Katherine J. ;

Lai, Zhongwu ;

Fisher, Paul R. ;

Meador, Catherine B. ;

Spitzler, Paula ;

Ichihara, Eiki ;

Ross, Sarah J. ;

Ahdesmaki, Miika J. ;

Ahmed, Ambar ;

Ratcliffe, Laura E. ;

O'Brien, Elizabeth L. Christey ;

Barnes, Claire H. ;

Brown, Henry ;

Smith, Paul D. ;

Dry, Jonathan R. ;

Beran, Garry ;

Thress, Kenneth S. ;

Dougherty, Brian ;

Pao, William ;

Cross, Darren A. E. .

CANCER RESEARCH, 2015, 75 (12) :2489-2500

[5] 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

[6] Quinazoline-urea, new protein kinase inhibitors in treatment of prostate cancer [J].

Garofalo, Antonio ;

Goossens, Laurence ;

Lemoine, Amelie ;

Farce, Amaury ;

Arlot, Yannick ;

Depreux, Patrick .

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2010, 25 (02) :158-171

[7] Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors [J].

Gazdar, A. F. .

ONCOGENE, 2009, 28 :S24-S31

[8]

Jemal A, 2011, CA-CANCER J CLIN, V61, P134, DOI [10.3322/caac.20115, 10.3322/caac.21492, 10.3322/caac.20107]

[9] Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors [J].

Jia, Yong ;

Yun, Cai-Hong ;

Park, Eunyoung ;

Rcan, Dalia E. ;

Manuia, Mari ;

Juarez, Jose ;

Xu, Chunxiao ;

Rhee, Kevin ;

Chen, Ting ;

Zhang, Haikuo ;

Palakurthi, Sangeetha ;

Jang, Jaebong ;

Lelais, Gerald ;

DiDonato, Michael ;

Bursulaya, Badry ;

Michellys, Pierre-Yves ;

Epple, Robert ;

Marsilje, Thomas H. ;

McNeill, Matthew ;

Lu, Wenshuo ;

Harris, Jennifer ;

Bender, Steven ;

Wong, Kwok-Kin ;

Janne, Pasi A. ;

Eck, Michael J. .

NATURE, 2016, 534 (7605) :129-+

[10] Vandetanib (ZD6474), a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinases: Current Status and Future Directions [J].

Morabito, Alessandro ;

Piccirillo, Maria Carmela ;

Falasconi, Fabiano ;

De Feo, Gianfranco ;

Del Giudice, Antonia ;

Bryce, Jane ;

Di Maio, Massimo ;

De Maio, Ermelinda ;

Normanno, Nicola ;

Perrone, Francesco .

ONCOLOGIST, 2009, 14 (04) :378-390

← 1 2 3 →