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)导致几个突变的和耐Flt3的AML细胞系和AML患者的原代母细胞发生坏死。我们已经开发了TRND00507679和TRND00421925的纳米颗粒配方，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。TRND00507679包裹的纳米颗粒(TRND00507679-NPs)在体内乳腺癌Ehrlich腹水瘤(EAT)模型中显示出剂量依赖性的抑制肿瘤生长。此外，我们还比较了PI3K-Delta抑制剂Idelalisib纳米粒子(Idelalisib-NPs)和TRND00507679-NPs对肿瘤生长的抑制作用。与Idelalisib-NPs相比，治疗小鼠EAT肿瘤与TRND00507679-NPs显著减少肿瘤生长有关。 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。此外，Hillstream Biophma，Inc.和NCATS正在为这些纳米配方的PI3KDelta-HDAC6双重抑制剂申请联合发明专利。

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 developed the nano-particle formulation for TRND00507679 and TRND00421925 and studied their cellular uptake and anti-proliferative activity in several human cancer cell lines. TRND00507679 encapsulated nano-particles (TRND00507679-NPs) displayed a dose-dependent inhibition of tumor growth in an in vivo breast cancer Ehrlich ascites tumor (EAT) model. Additionally, we have also compared the tumor growth inhibition caused by PI3K-delta inhibitor, Idelalisib based nano-particles (Idelalisib-NPs) with that of TRND00507679-NPs. In contrast to Idelalisib-NPs, treatment of EAT tumors in mice was associated with substantial reduction in tumor growth by TRND00507679-NPs. Work to date has resulted in a publication in the Journal of Medicinal Chemistry and submission of an international patent application. Additionally, filing of a joint inventorship patent between Hillstream Biopharma, Inc. and NCATS for these nano-formulated PI3Kdelta-HDAC6 dual inhibitors is currently underway.