HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers

我们设计并合成了新的双HDAC/PI3K抑制剂，确定了几种新的分子，以个位数纳米摩尔的效力抑制两个靶点。选定的化合物已在NCI60细胞系组中进行了测试，显示出几种细胞系的抗增殖和细胞杀伤活性。在基于细胞的靶标结合试验中检测了其中的一部分，证实了双重抑制剂可以同时作用于细胞中的PI3K-delta和HDAC6。先导化合物（TRND00507679）可诱导几种突变型和flt3耐药AML细胞系以及来自AML患者的原代细胞坏死。我们开发了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封装纳米颗粒（TRND00507679- nps）在体内乳腺癌埃利希腹水瘤（EAT）模型中显示出剂量依赖性的肿瘤生长抑制作用。此外，我们还比较了PI3K-delta抑制剂Idelalisib基纳米颗粒（Idelalisib- nps）与TRND00507679-NPs对肿瘤生长的抑制作用。与Idelalisib-NPs相比，TRND00507679-NPs治疗小鼠EAT肿瘤可显著降低肿瘤生长。

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.