Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9

被引：18

作者：

Rye, Carl S. ^{[1
]}

Chessum, Nicola E. A. ^{[1
]}

Lamont, Scott ^{[2
]}

Pike, Kurt G. ^{[2
]}

Faulder, Paul ^{[2
]}

Demeritt, Julie ^{[2
]}

Kemmitt, Paul ^{[2
]}

Tucker, Julie ^{[2
,3
]}

Zani, Lorenzo ^{[1
]}

Cheeseman, Matthew D. ^{[1
]}

Isaac, Rosie ^{[2
]}

Goodwin, Louise ^{[2
]}

Boros, Joanna ^{[2
]}

Raynaud, Florence ^{[1
]}

Hayes, Angela ^{[1
]}

Henley, Alan T. ^{[1
]}

de Billy, Emmanuel ^{[1
]}

Lynch, Christopher J. ^{[1
]}

Sharp, Swee Y. ^{[1
]}

Poele, Robert Te ^{[1
]}

O'Fee, Lisa ^{[1
]}

Foote, Kevin M. ^{[2
]}

Green, Stephen ^{[2
]}

Workman, Paul ^{[1
]}

Jones, Keith ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Canc Therapeut Unit, London SW7 3RP, England

[2] AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[3] Newcastle Univ, Northern Inst Canc Res, Sch Med, Paul OGorman Bldg,Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

来源：

MEDCHEMCOMM | 2016年 / 7卷 / 08期

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; DEPENDENT KINASE INHIBITOR; DINACICLIB SCH 727965; MOLECULAR CHAPERONES; ANTICANCER AGENTS; CANCER-THERAPY; BINDING-SITE; PROTEOSTASIS; METASTASIS; PROTEIN;

D O I：

10.1039/c6md00159a

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：

Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 mu M). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM).

引用

页码：1580 / 1586

页数：7

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