Preclinical anti‐myeloma activity of the novel HDAC‐inhibitor JNJ‐26481585

Abstract

Summary Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti‐cancer agents and may be useful to enhance the therapeutic efficiency of established anti‐myeloma treatments. This study preclinically evaluated the effects of the ‘second generation’ pan‐HDAC inhibitor JNJ‐26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n = 42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2‐family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl‐1 depletion and Hsp72 induction were the most reliable features observed in JNJ‐26481585‐treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ‐26481585 with anti‐myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC‐inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

“…[21][22][23][24][25][26]29,30,50 The novel HDACi JNJ-26481585 has been described to have an improved pharmacodynamic profile with sustained activity. 38,39 We showed that JNJ-26481585 is able to upregulate SMN protein levels in vitro. Our results in primary patient fibroblast cell lines indicate that, as previously demonstrated for LBH589 and VPA, 22,26 JNJ-26481585 acts on SMN2 transcription and influences correct splicing.…”

“…38,39 Its marked potency (IC 50 ¼ 0.16 nmol/l) as well as its continued activity in solid tissue makes it an interesting candidate for SMA therapy. ELISA analysis showed that JNJ-26481585 is more effective at a 4 Â lower dose of 100 nM for 64 h in upregulating SMN2 protein expression than LBH589, a structurally similar HDACi, shown to be highly efficient in upregulation of SMN 26 (Figure 1a).…”

“…26 The improved pharmacological profile and increased half-life of JNJ-26481585 as compared with LBH589 prompted us to test this compound in vitro and in vivo for its benefit on SMA. 38,39 For in vivo analysis, we used a severe SMA mouse model developed by a Taiwanese group. 40 An efficient breeding scheme (Smn À/ À ; SMN2 tg/tg X Smn þ / À ) developed in our laboratory resulted in 50% of each litter developing SMA (Smn À/ À ; SMN2 tg/0 ) with a mean survival of B10 days on pure FVB/N background.…”

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…A number of HDACi, including CR2408 (broad acting), JNJ-26481585 (broad acting) ACY-1215 (targets HDAC 6) and panobinostat (broad acting), have shown promise for the treatment of MM with some inhibitors now in clinical trials, or used in the clinic [107][108][109][110]. However, to date, there…”

The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma

“…11,17,18 Transfection of INA-6 and MM.1S cells with short-interfering RNA expression plasmids PSUPER-derived short interfering (si) RNA expression constructs were designed according to previously described guidelines. 19 The sequences of the sense oligonucleotides of the most effective siRNA are provided in the Online Supplementary Design and Methods.…”