(12MA030) HDAC6:Small Molecule Histone Deacetylase 6 Inhibitor with a Substituted Aryl Urea Cap Group

Novel, selective, small molecule inhibitors of histone deacetylase 6 (HDAC6) activity. The most promising molecule inhibits HDAC6 activity with an IC50 of 2.5nM in vitro. In a series of compounds, higher binding specificity for HDAC6 correlated with st…

Novel, selective, small-molecule inhibitors of histone deacetylase 6 (HDAC6) activity. The most promising molecule inhibits HDAC6 activity with an IC50 of 2.5nM in vitro. In a series of compounds, higher binding specificity for HDAC6 correlated with stronger antiproliferative activity. The lead inhibitor significantly slows melanoma tumor growth in a mouse xenograft model significantly better than Tubastatin A, another HDAC6 inhibitor. Tubastatin A has also been shown to strongly inhibit mantle cell lymphoma growth in a mouse xenograft model.

Abstract:

  • Our lead HDAC6 inhibitor is active against melanoma cells and may show efficacy against mantle cell lymphoma, organ transplant rejection, and Charcot–Marie–Tooth disease.
  • The market size for advanced metastatic melanoma therapies can be estimated from vemurafenib, a mutant-Raf kinase inhibitor, and ipilimumab, a T-cell targeted immunotherapy, that have world-wide annualized revenues of $282MM and $648MM, respectively.
  • Better drugs are needed because Vemurafenib has a high rate of resistance within 7-9 months after initial response, and less than 25% of patients treated with ipilimumab respond and 90% of those will eventually relapse.
  • Many HDAC inhibitors are in development, and two pan-HDAC inhibitors, Merck’s vorinostat and Celgene’s romidepsin, have been approved for the treatment of lymphoma with 2012 annualized revenues for romidepsin of $50MM.
  • The attractiveness of this target is evidenced by Celgene’s recent $100MM deal with Acetylon for the rights to 3 drug candidates including ACY-1215, a selective HDAC6 inhibitor. This deal follows Celgene’s $15MM equity investment in Acetylon in Feb 2012.
  • Our lead HDAC6 inhibitor is active against melanoma cells and may show efficacy against mantle cell lymphoma, organ transplant rejection, and Charcot–Marie–Tooth disease.
  • The market size for advanced metastatic melanoma therapies can be estimated from vemurafenib, a mutant-Raf kinase inhibitor, and ipilimumab, a T-cell targeted immunotherapy, that have world-wide annualized revenues of $282MM and $648MM, respectively.
  • Better drugs are needed because Vemurafenib has a high rate of resistance within 7-9 months after initial response, and less than 25% of patients treated with ipilimumab respond and 90% of those will eventually relapse.
  • Many HDAC inhibitors are in development, and two pan-HDAC inhibitors, Merck’s vorinostat and Celgene’s romidepsin, have been approved for the treatment of lymphoma with 2012 annualized revenues for romidepsin of $50MM.
  • The attractiveness of this target is evidenced by Celgene’s recent $100MM deal with Acetylon for the rights to 3 drug candidates including ACY-1215, a selective HDAC6 inhibitor. This deal follows Celgene’s $15MM equity investment in Acetylon in Feb 2012.

Website:

https://moffitt.org/research-science/academic-and-industry-partnerships/office-of-innovation/available-technologies/pharmaceuticals-biologics/12ma030-hdac6small-molecule-histone-deacetylase-6-inhibitor-with-a-substituted-aryl-urea-cap-group/