MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells

JNJ-26481585, a Novel Second-Generation Oral Histone Deacetylase Inhibitor, Shows Broad-Spectrum Preclinical Antitumoral Activity

“…It should be noted though that other HDAC family members also regulate Hsp90. The class I-specific HDAC inhibitors MS-275 and depsipeptide disrupt Hsp90 function in an indirect manner, through HDAC1-mediated acetylation and inhibition of Hsp70 function (38,39). Similarly, Park et al (40) showed that knockdown of HDAC10 resulted in depletion of Hsp90 client vascular endothelial growth factor receptor.…”

TAp73 Protein Stability Is Controlled by Histone Deacetylase 1 via Regulation of Hsp90 Chaperone Function

“…The stable RKO cell line that inducibly expresses HDAC1 shRNA was generated based on the Tet-on inducible system as previously described (64). Briefly, pTER vector that can express an shRNA against HDAC1 driven by the tetracycline-regulated polymerase III promoter generated in a previous study (40) was transfected into parental RKO cells expressing a Tet Repressor (pcDNA6) (63).…”

“…In addition to TAp73, inactivation of Hsp90 upon treatment of HDACI or knockdown of HDAC1 enhances proteasomal degradation of Her-2, FLT-3, and DNMT1 (62)(63)(64). Furthermore, inhibition of HDAC6, a class II HDAC member, and subsequent inactivation of Hsp90 led to enhanced degradation of glucocorticoid receptor, Bcr-Abl, and mutant p53 (46,55,65).…”

FLT3 as a therapeutic target in AML: still challenging after all these years

“…Furthermore, synergistic effects have been demonstrated in combination with the heat shock protein-90 inhibitor 17-AAG and the histone deacetylases inhibitor MS-275. 100,101 However, the sequence of administration, toxicity profiles, and optimal target combinations need to be defined.…”