Dysregulation of both Histone Deacetylase (HDAC) and Phosphatidylinositol-3-kinase (PI3K) is often involved in over-expression of oncogenes c-Myc and Cyclin D1, thereby promoting cell growth and proliferation. Dual inhibition of HDAC and PI3K is an emerging therapeutic approach for cancer as it offers the advantages of better efficacy resulting from synergy and overcoming the developed resistance. A series of pyrimidine-amine/purine based hydroxamic acids were designed and synthesized as dual inhibitors of Histone Deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) enzymes. Structure Activity Relationships (SAR) were explored to develop highly potent PI3Kd and HDAC6 selective inhibitors (IC50 &lt; 10 nM against both enzymes) with good ADME profile. In vitro screening against a panel of 60 different cancer cell lines at National Cancer Institute (NCI) revealed several hit molecules with potent cell-kill activity against various cancer cell lines including Leukemia, Melanoma, Renal, Non-small cell lung cancer, Central Nervous System (CNS) cancer and Breast cancer.

Design, synthesis and in vitro evaluation of dual inhibitors of phosphatidylinositol-3-kinase delta (PI3Kd) and histone deacetylase 6 (HDAC6)

256th National Meeting (2018)

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