HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers

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We have designed and synthesized novel dual HDAC/PI3K inhibitors, identifying several novel molecules that inhibit both targets with single digit nanomolar potency. Selected compounds have been tested in the NCI60 cell line panel, showing anti-proliferation and cell-killing activity in several cell lines. A subset of these were examined in cell-based target engagement assays, confirming that the dual inhibitors engage both PI3K-delta and HDAC6 in cells. The lead compound, TRND00507679, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients. We have scaled up the synthesis of TRND00507679 and submitted it to our collaborator at Dana-Farber Cancer Institute for an in vivo anti-AML efficacy study in mice. We have also completed development of the nano-particle formulation for TRND00507679 and TRND00421925 and studied their cellular uptake and anti-proliferative activity in several human cancer cell lines. Work to date has resulted in a publication in the Journal of Medicinal Chemistry and submission of an international patent application.