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CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells

Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5-100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

 

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The study described here aimed to identify a potential therapeutic option for Neurofibromatosis Type 2 (NF2), a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. The researchers screened for inhibitors of the phosphoinositide-3 kinase (PI3K) pathway, a druggable target, and identified CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, as the lead compound.

The researchers evaluated the effects of CUDC907 on human schwannoma cells in vitro and in vivo. They found that CUDC907 selectively reduced the viability of human merlin deficient Schwann cells (MD-SCs) compared to wild-type cells, promoted cell cycle arrest and caspase-3/7 activation, and decreased levels of pAKT and YAP. The researchers also observed a decrease in tumor growth rate in a 14-day treatment regimen and a decrease in YAP levels in a mouse model.

Further evaluation in five primary vestibular schwannomas (VS) showed that CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. The efficacy of CUDC907 correlated with basal phospho-HDAC2 levels.

Overall, these findings suggest that CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and may be a promising candidate for clinical trials.

Related Products

Cat.No. Product Name Information
S2759 Fimepinostat (CUDC-907) CUDC-907 is a dual PI3K and HDAC inhibitor for PI3Kα and HDAC1/2/3/10 with IC50 of 19 nM and 1.7 nM/5 nM/1.8 nM/2.8 nM, respectively. CUDC-907 induces cell cycle arrest and apoptosis in breast cancer cells. Phase 1.

Related Targets

Apoptosis related HDAC PI3K