HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers

我们已经设计并合成了新型的双重HDAC/PI 3 K抑制剂，鉴定了几种新型分子，其以个位数纳摩尔效力抑制两种靶标。已在NCI 60细胞系组中测试了选定的化合物，在几种细胞系中显示出抗增殖和细胞杀伤活性。在基于细胞的靶标接合测定中检查了其中的一个子集，证实了双重抑制剂在细胞中接合PI 3 K-δ和HDAC 6。先导化合物（TRND 00507679）在几种突变型和FLT 3耐药AML细胞系和AML患者的原代母细胞中诱导坏死。我们已经开发了TRND 00507679和TRND 00421925的纳米颗粒制剂，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。TRND 00507679包封的纳米颗粒（TRND 00507679-NP）在体内乳腺癌埃利希腹水肿瘤（EAT）模型中显示出对肿瘤生长的剂量依赖性抑制。此外，我们还比较了由PI 3 K-δ抑制剂、基于Idelalisib的纳米颗粒（Idelalisib-NP）与TRND 00507679-NP引起的肿瘤生长抑制。 与Idelalisib-NP相反，小鼠中EAT肿瘤的治疗与TRND 00507679-NP显著降低肿瘤生长相关。 迄今为止的工作成果已在《药物化学杂志》上发表，并提交了一项国际专利申请。此外，Hillstream Bioburma，Inc.和NCATS这些纳米配方PI 3 Kdelta-HDAC 6双重抑制剂目前正在进行中。

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.