HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers

我们设计和合成了新型的双HDAC/PI3K抑制剂，鉴定了几个新的分子，它们以个位数的纳摩尔效力抑制这两个靶点。选定的化合物已经在NCI60细胞系面板中进行了测试，在几种细胞系中显示出抗增殖和细胞杀伤活性。在基于细胞的靶结合分析中检查了其中的一个子集，证实了双重抑制物在细胞中同时结合了PI3K-Delta和HDAC6。先导化合物TRND00507679可以诱导几个突变的和耐Flt3的AML细胞株和AML患者的原代母细胞发生坏死。我们已经放大了TRND00507679的合成，并将其提交给我们在Dana-Farber癌症研究所的合作者，用于在小鼠身上进行体内抗AML疗效研究。我们还完成了TRND00507679和TRND00421925的纳米颗粒配方的开发，并研究了它们在几种人类癌细胞系中的细胞摄取和抗增殖活性。到目前为止的工作已经导致在《药物化学杂志》上发表了一篇文章，并提交了一项国际专利申请。

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.