Structure-based design and discovery of potent and selective KDM5 inhibitors

被引：39

作者：

Nie, Zhe ^{[1
]}

Shi, Lihong ^{[1
]}

Lai, Chon ^{[1
]}

O'Connell, Shawn M. ^{[1
,3
]}

Xu, Jiangchun ^{[1
]}

Stansfield, Ryan K. ^{[1
,4
]}

Hosfield, David J. ^{[2
]}

Veal, James M. ^{[1
,4
]}

Stafford, Jeffrey A. ^{[1
,4
]}

机构：

[1] Celgene Corp, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA

[2] Univ Chicago, Ben May Dept Canc Res, 929 East 57th St, Chicago, IL 60637 USA

[3] Pfizer Inc, Groton, CT 06340 USA

[4] Jecure Therapeut, San Diego, CA USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 09期

关键词：

Epigenetics; Histone lysine demethylase; KDM5; Tri-methylated H3K4; Structure-based design; HISTONE DEMETHYLASES; CANCER; CELLS; MELANOMA; TARGETS;

D O I：

10.1016/j.bmcl.2018.03.083

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：1490 / 1494

页数：5

共 50 条

[21] Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors
Barsanti, Paul A.
Pan, Yue
Lu, Yipin
Jain, Rama
Cox, Matthew
Aversa, Robert J.
Dillon, Michael P.
Ening, Robert
Hu, Cheng
Jin, Xianming
Knapp, Mark
Lan, Jiong
Ramurthy, Savithri
Rudewicz, Patrick
Setti, Lina
Subramanian, Sharadha
Mathur, Michelle
Taricani, Lorena
Thomas, George
Xiao, Linda
Yue, Qin
ACS MEDICINAL CHEMISTRY LETTERS, 2015, 6 (01): : 42 - 46
[22] Structure-Based Design of 2-Aminopyridine Oxazolidinones as Potent and Selective Tankyrase Inhibitors
Huang, Hongbing
Guzman-Perez, Angel
Acquaviva, Lisa
Berry, Virginia
Bregman, Howard
Dovey, Jennifer
Gunaydin, Hakan
Huang, Xin
Huang, Liyue
Saffran, Doug
Serafino, Randy
Schneider, Steve
Wilson, Cindy
DiMauro, Erin F.
ACS MEDICINAL CHEMISTRY LETTERS, 2013, 4 (12): : 1218 - 1223
[23] Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3
Boyd, Scott
Brookfield, Joanna L.
Critchlow, Susan E.
Cumming, Iain A.
Curtis, Nicola J.
Debreczeni, Judit
Degorce, Sebastien L.
Donald, Craig
Evans, Nicola J.
Groombridge, Sam
Hopcroft, Philip
Jones, Neil P.
Kettle, Jason G.
Lamont, Scott
Lewis, Hilary J.
MacFaull, Philip
McLoughlin, Sheila B.
Rigoreau, Laurent J. M.
Smith, James M.
St-Gallay, Steve
Stock, Julie K.
Turnbull, Andrew P.
Wheatley, Edward R.
Winter, Jon
Wingfield, Jonathan
JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (08) : 3611 - 3625
[24] Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors
Read, M
Harrison, RJ
Romagnoli, B
Tanious, FA
Gowan, SH
Reszka, AP
Wilson, WD
Kelland, LR
Neidle, S
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (09) : 4844 - 4849
[25] Structure-based design of highly potent and selective Cdk4 inhibitors.
Honma, T
Hayashi, K
Yoshizumi, T
Ikeura, C
Ikuta, M
Suzuki-Takahashi, I
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2003, 226 : U437 - U438
[26] Structure-based design and discovery of orally bioavailable potent nonbenzamidine factor Xa inhibitors.
Lam, PYS
Li, RH
Clark, CG
Pinto, DJ
Alexander, RS
Rossi, KA
Knabb, RM
Wong, PC
Aungst, BJ
Bai, SA
Wright, MR
Wexler, RR
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 219 : U31 - U31
[27] Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors
Labadie, Sharada S.
Dragovich, Peter S.
Cummings, Richard T.
Deshmukh, Gauri
Gustafson, Amy
Han, Ning
Harmange, Jean-Christophe
Kiefer, James R.
Li, Yue
Liang, Jun
Liederer, Bianca M.
Liu, Yichin
Manieri, Wanda
Mao, Wiefeng
Murray, Lesley
Ortwine, Daniel F.
Trojer, Patrick
VanderPorten, Erica
Vinogradova, Maia
Wen, Li
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (18) : 4492 - 4496
[28] The development of therapeutic inhibitors of the KDM5 histone demethylases
Hudlebusch, Heidi R.
Heinemann, Bo
Nielsen, Jesper M.
Kleine-Kohlbrecher, Daniela
Hauge, Camilla
Boesen, Thomas
Labelle, Marc
Gerlach, Lars-Ole
Staller, Peter
Birk, Peter
CANCER RESEARCH, 2014, 74 (19)
[29] Structure-based discovery of new selective small-molecule sirtuin 5 inhibitors
Liu, Sha
Ji, Sen
Yu, Zhu-Jun
Wang, Hua-Li
Cheng, Xu
Li, Wei-Jian
Jing, Li
Yu, Yamei
Chen, Qiang
Yang, Ling-Ling
Li, Guo-Bo
Wu, Yong
CHEMICAL BIOLOGY & DRUG DESIGN, 2018, 91 (01) : 257 - 268
[30] Structure-based discovery of potent inhibitors of human asparagine synthetase.
Koroniak, L
Gutierrez, JA
Humkey, R
Richards, NGJ
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2004, 227 : U903 - U903

← 1 2 3 4 5 →