HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers

HDAC/PI3K 双重抑制剂治疗罕见癌症

基本信息

项目摘要

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.
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。

项目成果

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专利数量(1)

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Donald Lo其他文献

Donald Lo的其他文献

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{{ truncateString('Donald Lo', 18)}}的其他基金

Studies of Tumor-Penetrating Microparticles for Pancreatic Cancer
肿瘤穿透微粒治疗胰腺癌的研究
  • 批准号:
    10470633
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
Studies of Tumor-Penetrating Microparticles for Pancreatic Cancer
肿瘤穿透微粒治疗胰腺癌的研究
  • 批准号:
    10685882
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
Evaluation of ACT1 to Treat Diabetic Keratopathy
ACT1 治疗糖尿病角膜病的评价
  • 批准号:
    10470634
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
Helping to End Addiction Long-term (HEAL): Development of Clinical Candidate Drugs for Pain, Addiction and Overdose
帮助长期戒除成瘾 (HEAL):开发治疗疼痛、成瘾和药物过量的临床候选药物
  • 批准号:
    10686744
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
COVID-19: Identification and Development of Clinical Candidates to Treat SARS-CoV-2
COVID-19:识别和开发治疗 SARS-CoV-2 的临床候选药物
  • 批准号:
    10686748
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers
HDAC/PI3K 双重抑制剂治疗罕见癌症
  • 批准号:
    10259368
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
COVID-19: Identification and Development of Clinical Candidates to Treat SARS-CoV-2
COVID-19:识别和开发治疗 SARS-CoV-2 的临床候选药物
  • 批准号:
    10259371
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
HEAL: Development of Clinical Candidate Drugs for Pain, Addiction and Overdose
HEAL:开发治疗疼痛、成瘾和药物过量的临床候选药物
  • 批准号:
    10259369
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
Gene Therapy Platform for Rare Diseases
罕见病基因治疗平台
  • 批准号:
    10259364
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:
Development of Nogo Receptor Decoy for the Treatment of Spinal Cord Injury
用于治疗脊髓损伤的 Nogo 受体诱饵的开发
  • 批准号:
    10686732
  • 财政年份:
  • 资助金额:
    $ 107.1万
  • 项目类别:

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