In vitro: WT161 selectively inhibits HDAC6 and dramatically increases levels of acetylated α-tubulin (Ac-α-tubulin) with little effect on global lysine acetylation. WT161 induces significant toxicity in all multiple myeloma cell lines tested, with IC50s between 1.5 and 4.7 μM . WT161 in combination with bortezomib triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment is effective in bortezomib-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate multiple myeloma cell drug resistance. In vivo: WT161 shows toxicity at 100 mg/kg i.p., but WT161 is well tolerated at 50 mg/kg i.p.. Bortezomib combined with WT161 demonstrates a significant antitumor effect.
|Cell lines||MM cells|
|Preparation method||Cells cultured with WT161, BTZ, and CFZ were harvested, washed, and lysed using lysis buffer, and complete protease inhibitor mixture.|
|Incubation time||6 h|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||100 mg/mL in DMSO|
Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma.
Hideshima T, et al. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13162-13167. PMID: 27799547.
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ACY-738 is a potent, selective and orally-bioavailable HDAC6 inhibitor, with an IC50s of 1.7 nM.
HPOB is a highly potent and selective inhibitor of histone deacetylase 6 (HDAC6) with IC50 of 56 nM, >30 fold less potent against other HDACs.
HDAC8-IN-1 is a HDAC8 inhibitor with an IC50 of 27.2 nM in cancer cell lines.
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