8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

被引：74

作者：

Bavetsias, Vassilios ^{[1
]}

Lanigan, Rachel M. ^{[1
]}

Ruda, Gian Filippo ^{[2
,3
]}

Atrash, Butrus ^{[1
]}

McLaughlin, Mark G. ^{[1
]}

Tumber, Anthony ^{[2
,3
]}

Mok, N. Yi ^{[1
]}

Le Bihan, Yann-Vai ^{[1
]}

Dempster, Sally ^{[1
]}

Boxall, Katherine J. ^{[1
]}

Jeganathan, Fiona ^{[1
]}

Hatch, Stephanie B. ^{[2
,3
]}

Savitsky, Pavel ^{[2
]}

Velupillai, Srikannathasan ^{[2
]}

Krojer, Tobias ^{[2
]}

England, Katherine S. ^{[2
,3
]}

Sejberg, Jimmy ^{[1
]}

Thai, Ching ^{[1
]}

Donovan, Adam ^{[1
]}

Pal, Akos ^{[1
]}

Scozzafava, Giuseppe ^{[2
,3
]}

Bennett, James M. ^{[2
,3
]}

Kawamura, Akane ^{[4
]}

Johansson, Catrine ^{[2
,5
]}

Szykowska, Aleksandra ^{[2
]}

Gileadi, Carina ^{[2
]}

Burgess-Brown, Nicola A. ^{[2
]}

von Delft, Frank ^{[2
,6
,7
]}

Oppermann, Udo ^{[2
,5
]}

Walters, Zoe ^{[8
,9
]}

Shipley, Janet ^{[8
,9
]}

Raynaud, Florence I. ^{[1
]}

Westaway, Susan M. ^{[10
]}

Prinjha, Rab K. ^{[10
]}

Fedorov, Oleg ^{[2
,3
]}

Burke, Rosemary ^{[1
]}

Schofield, Christopher J. ^{[4
]}

Westwood, Isaac M. ^{[1
]}

Bountra, Chas ^{[2
]}

Mueller, Susanne ^{[2
,3
]}

van Montfort, Rob L. M. ^{[1
]}

Brennan, Paul E. ^{[2
,3
]}

Blagg, Julian ^{[1
]}

机构：

[1] Inst Canc Res, Cancer Res UK Canc Therapeut Unit, 15 Cotswold Rd, London SM2 5NG, England

[2] Univ Oxford, SGC, ORCRB Roosevelt Dr, Oxford OX3 7DQ, England

[3] Univ Oxford, Nuffield Dept Med, TDI, NDMRB Roosevelt Dr, Oxford OX3 7FZ, England

[4] Univ Oxford, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England

[5] NIHR Oxford Biomed Res Unit, Botnar Res Ctr, Oxford OX3 7LD, England

[6] DLS, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England

[7] Univ Johannesburg, Dept Biochem, ZA-2006 Auckland Pk, South Africa

[8] Inst Canc Res, Div Mol Pathol, London SM2 5NG, England

[9] Inst Canc Res, Div Canc Therapeut, London SM2 5NG, England

[10] GlaxoSmithKline R&D, Epinova Discovery Performance Unit, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 04期

基金：

巴西圣保罗研究基金会; 英国惠康基金; 英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会; 加拿大创新基金会;

关键词：

STRUCTURE VALIDATION; ALDEHYDE OXIDASE; PROSTATE-CANCER; PROTEINS; MOLPROBITY;

D O I：

10.1021/acs.jmedchem.5b01635

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fell) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me(3) and H3K4Me(3) demethylation in a cell-based assay.

引用

页码：1388 / 1409

页数：22

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