Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR

被引：40

作者：

Basu, Debjit ^{[1
]}

Richters, Andre ^{[1
]}

Rauh, Daniel ^{[1
]}

机构：

[1] Tech Univ Dortmund, Dept Chem & Chem Biol, D-44227 Dortmund, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 12期

关键词：

Kinases; Medicinal chemistry; Receptor tyrosine kinases; Lung cancer; Covalent-Reversible Inhibitor; EPIDERMAL-GROWTH-FACTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; PHASE-II TRIAL; IRREVERSIBLE INHIBITORS; RECEPTOR; GEFITINIB; MUTATIONS; POTENT; T790M;

D O I：

10.1016/j.bmc.2015.04.038

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：

The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the application of fine-tuned covalent drugs. Here we report the design, synthesis and biochemical evaluation of a novel class of EGFR inhibitors with a covalent yet reversible warhead. A series of WZ4002 analogs, derived from anilinopyrimidine and 3-substituted-2-cyanoacrylamide scaffolds, exhibit strong and selective inhibitory activity against clinically relevant EGFR(L858R) and EGFR(L858R/T790M). (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：2767 / 2780

页数：14

共 39 条

[1] Structure-guided development of affinity probes for tyrosine kinases using chemical genetics [J].

Blair, Jimmy A. ;

Rauh, Daniel ;

Kung, Charles ;

Yun, Cai-Hong ;

Fan, Qi-Wen ;

Rode, Haridas ;

Zhang, Chao ;

Eck, Michael J. ;

Weiss, William A. ;

Shokat, Kevan M. .

NATURE CHEMICAL BIOLOGY, 2007, 3 (04) :229-238

[2] Opinion - Drug-target residence time and its implications for lead optimization [J].

Copeland, Robert A. ;

Pompliano, David L. ;

Meek, Thomas D. .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (09) :730-739

[3] 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

[4] Nitric oxide donating anilinopyrimidines: Synthesis and biological evaluation as EGFR inhibitors [J].

Han, Chun ;

Huang, Zhangjian ;

Zheng, Chao ;

Wan, Ledong ;

Lai, Yisheng ;

Peng, Sixun ;

Ding, Ke ;

Ji, Hongbin ;

Zhang, Yihua .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2013, 66 :82-90

[5] Novel Hybrids of (Phenylsulfonyl)furoxan and Anilinopyrimidine as Potent and Selective Epidermal Growth Factor Receptor Inhibitors for Intervention of Non-Small-Cell Lung Cancer [J].

Han, Chun ;

Huang, Zhangjian ;

Zheng, Chao ;

Wan, Ledong ;

Zhang, Lianwen ;

Peng, Sixun ;

Ding, Ke ;

Ji, Hongbin ;

Tian, Jide ;

Zhang, Yihua .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (11) :4738-4748

[6] Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme [J].

Hayashi, Y ;

Ueki, K ;

Waha, A ;

Wiestler, OD ;

Louis, DN ;

vonDeimling, A .

BRAIN PATHOLOGY, 1997, 7 (03) :871-875

[7] Epidermal Growth Factor Receptor (EGFR) Signaling and Covalent EGFR Inhibition in Lung Cancer [J].

Heuckmann, Johannes M. ;

Rauh, Daniel ;

Thomas, Roman K. .

JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (27) :3417-3420

[8] LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both [J].

Katakami, Nobuyuki ;

Atagi, Shinji ;

Goto, Koichi ;

Hida, Toyoaki ;

Horai, Takeshi ;

Inoue, Akira ;

Ichinose, Yukito ;

Koboyashi, Kunihiko ;

Takeda, Koji ;

Kiura, Katsuyuki ;

Nishio, Kazuto ;

Seki, Yoko ;

Ebisawa, Ryuichi ;

Shahidi, Mehdi ;

Yamamoto, Nobuyuki .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (27) :3335-+

[9] Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis [J].

Krishnan, Shyam ;

Miller, Rand M. ;

Tian, Boxue ;

Mullins, R. Dyche ;

Jacobson, Matthew P. ;

Taunton, Jack .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136 (36) :12624-12630

[10] Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors:: Synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N′-{4-[4-quinolyloxy)phenyl}ureas [J].

Kubo, K ;

Shimizu, T ;

Ohyama, S ;

Murooka, H ;

Iwai, A ;

Nakamura, K ;

Hasegawa, K ;

Kobayashi, Y ;

Takahashi, N ;

Takahashi, K ;

Kato, S ;

Izawa, T ;

Isoe, T .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (05) :1359-1366

← 1 2 3 4 →