Identification of small-molecule HSF1 amplifiers by high content screening in protection of cells from stress induced injury.
Small molecule amplifiers of heat shock response have shown promising results in rescuing stress related injury through chaperone amplification. Herein, we report the results of a high content target-based primary screening of several known bioactive libraries. Screening resulted in the identification of three potent gedunin derivatives and a sappanone A derivative. Western blot results confirmed compound-induced activation of HSF1 and increased expression level of HSP70. These compounds rescued cells from cell death caused by proteasome inhibitor MG-132 and RNAi knockdown of HSF1 significantly reversed the cytoprotective effects, confirming an HSF1-dependent mechanism of action. These HSF1 amplifiers were tested in two mammalian cell based models of Huntington's disease (HD) and found to improve survival. Therefore, these screening hits may have therapeutic potential for HD and possibly other protein conformational disorders.
Department of Biology, CytRx Corporation, San Diego, CA 92109, USA. bzhang418@gmail.com
Bin
B
Zhang
Qingyan
Q
Au
Il Sang
IS
Yoon
Marie-Helene
MH
Tremblay
Gary
G
Yip
Yuefen
Y
Zhou
Jack R
JR
Barber
Shi Chung
SC
Ng
D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004353:Drug Evaluation, Preclinical; D020868:Gene Silencing; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D054852:Small Molecule Libraries; D013312:Stress, Physiological; D014157:Transcription Factors / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D054852:Small Molecule Libraries; D014157:Transcription Factors