Structural Biology-Inspired Discovery of Novel KRAS-PDEδ Inhibitors

被引：26

作者：

Jiang, Yan ^{[1
]}

Zhuang, Chunlin ^{[1
]}

Chen, Long ^{[1
]}

Lu, Junjie ^{[1
]}

Dong, Guoqiang ^{[1
]}

Miao, Zhenyuan ^{[1
]}

Zhang, Wannian ^{[1
]}

Li, Jian ^{[2
]}

Sheng, Chunquan ^{[1
]}

机构：

[1] Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China

[2] East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 22期

基金：

中国国家自然科学基金;

关键词：

PROTEIN PRENYLATION; CANCER-THERAPY; RAS; TRANSPORT; MEMBRANE; SUBUNIT; GTPASES; BIND;

D O I：

10.1021/acs.jmedchem.7b01243

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structural biology is a powerful tool for investigating the stereospecific interactions between a protein and its ligand. Herein, an unprecedented chiral binding pattern was observed for inhibitors of KRAS-PDE delta interactions. Virtual screening and X-ray crystallography studies revealed that two enantiomers of a racemic inhibitor could bind at different sites. Fragment-based drug design was used to identify highly potent PDE delta inhibitors that can be used as promising lead compounds for target validation and antitumor drug development.

引用

页码：9400 / 9406

页数：7

共 28 条

[1] Targeting protein prenylation for cancer therapy [J].

Berndt, Norbert ;

Hamilton, Andrew D. ;

Sebti, Said M. .

NATURE REVIEWS CANCER, 2011, 11 (11) :775-791

[2] Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide [J].

Bisson, Claudine ;

Britton, K. Linda ;

Sedelnikova, Svetlana E. ;

Rodgers, H. Fiona ;

Eadsforth, Thomas C. ;

Viner, Russell C. ;

Hawkes, Tim R. ;

Baker, Patrick J. ;

Rice, David W. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2016, 55 (43) :13485-13489

[3] Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities [J].

Bournet, Barbara ;

Buscail, Camille ;

Muscari, Fabrice ;

Cordelier, Pierre ;

Buscail, Louis .

EUROPEAN JOURNAL OF CANCER, 2016, 54 :75-83

[4] Lipidated Ras and Rab peptides and proteins - Synthesis, structure, and function [J].

Brunsveld, Luc ;

Kuhlmann, Juergen ;

Alexandrov, Kirill ;

Wittinghofer, Alfred ;

Goody, Roger S. ;

Waldmann, Herbert .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2006, 45 (40) :6622-6646

[5] The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins [J].

Chandra, Anchal ;

Grecco, Hernan E. ;

Pisupati, Venkat ;

Perera, David ;

Cassidy, Liam ;

Skoulidis, Ferdinandos ;

Ismail, Shehab A. ;

Hedberg, Christian ;

Hanzal-Bayer, Michael ;

Venkitaraman, Ashok R. ;

Wittinghofer, Alfred ;

Bastiaens, Philippe I. H. .

NATURE CELL BIOLOGY, 2012, 14 (02) :148-158

[6] Synthesis of the Rheb and K-Ras4B GTPases [J].

Chen, Yong-Xiang ;

Koch, Sebastian ;

Uhlenbrock, Katharina ;

Weise, Katrin ;

Das, Debapratim ;

Gremer, Lothar ;

Brunsveld, Luc ;

Wittinghofer, Alfred ;

Winter, Roland ;

Triola, Gemma ;

Waldmann, Herbert .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2010, 49 (35) :6090-6095

[7] Ammonia-induced Na,K-ATPase/ouabain-mediated EGF receptor transactivation, MAPK/ERK and PI3K/AKT signaling and ROS formation cause astrocyte swelling [J].

Dai, Hongliang ;

Song, Dan ;

Xu, Junnan ;

Li, Baoman ;

Hertz, Leif ;

Peng, Liang .

NEUROCHEMISTRY INTERNATIONAL, 2013, 63 (06) :610-625

[8] Targeting ras signalling pathways in cancer therapy [J].

Downward, J .

NATURE REVIEWS CANCER, 2003, 3 (01) :11-22

[9] Therapeutic intervention based on protein prenylation and associated modifications [J].

Gelb, Michael H. ;

Brunsveld, Lucas ;

Hrycyna, Christine A. ;

Michaelis, Susan ;

Tamanoi, Fuyuhiko ;

Van Voorhis, Wesley C. ;

Waldmann, Herbert .

NATURE CHEMICAL BIOLOGY, 2006, 2 (10) :518-528

[10]

Ismail SA, 2011, NAT CHEM BIOL, V7, P942, DOI [10.1038/NCHEMBIO.686, 10.1038/nchembio.686]

← 1 2 3 →