WO2023202091A1 - Ampk抑制剂联合hdac抑制剂在制备肿瘤治疗的药物中的应用 - Google Patents

Ampk抑制剂联合hdac抑制剂在制备肿瘤治疗的药物中的应用 Download PDF

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WO2023202091A1
WO2023202091A1 PCT/CN2022/137379 CN2022137379W WO2023202091A1 WO 2023202091 A1 WO2023202091 A1 WO 2023202091A1 CN 2022137379 W CN2022137379 W CN 2022137379W WO 2023202091 A1 WO2023202091 A1 WO 2023202091A1
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万晓春
章桂忠
刘曌
程建
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Shenzhen Institute of Advanced Technology of CAS
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  • the invention belongs to the technical field of anti-tumor drugs, and specifically relates to the application of AMPK inhibitors combined with HDAC inhibitors in the preparation of drugs for tumor treatment.
  • Tumor is a non-hereditary genetic disease. Normal cells undergo genetic changes under the influence of tumorigenic factors and lose normal control of their growth, leading to abnormal proliferation. Tumor cells have three significant basic characteristics: immortality, migration and loss of contact inhibition. The core idea of tumor treatment is to kill and eliminate tumor cells. Currently, commonly used clinical cancer treatments include chemotherapy, radiotherapy, hormone therapy, molecular targeted therapy, immunotherapy, etc. But for almost all drugs, as the patient uses them for a long time, the cancer cells will become resistant to the drugs, causing the drugs to stop working on the cancer cells. This acquired resistance of tumor cells to drug treatment not only severely limits the effectiveness of clinical treatment, but is also the molecular basis of tumor recurrence. Therefore, we need to develop new treatment methods or optimize existing methods. On the one hand, they can break drug resistance and enhance anti-tumor effects. On the other hand, they can enrich our "arsenal" against tumors and broaden the range of choices for tumor treatment strategies.
  • Histone deacetylases are key gene expression regulators that inhibit gene transcription by removing histone acetylation modifications. Abnormal expression of HDACs has been observed in most tumors and is a potential target for tumor treatment.
  • HDCA-targeting inhibitors have been approved by the FDA for cutaneous T lymphoma (Cutaneous Treatment of tumors such as T-cell lymphoma) and multiple myeloma. Despite high hopes, the clinical efficacy is unsatisfactory and drug resistance occurs from time to time. In the treatment of solid tumors, a number of clinical trials are being carried out, but so far, there have been no successful cases (Reference: Amila Suraweera, Kenneth J.
  • Adenosine monophosphate-activated protein kinase is a cellular energy and nutrient sensor and plays a key role in cellular energy homeostasis and metabolic regulation.
  • the traditional view is that AMPK is a tumor suppressor under normal circumstances. In the early stages of cancer development, it can inhibit tumor growth through metabolic regulation or phosphorylation by mediating tumor suppressors such as TET2, p53, and TSC2.
  • TET2, p53, and TSC2 tumor suppressors
  • AMPK is up-regulated or activated in tumor cells under some special genetic states or metabolic stress conditions (such as hypoxia, nutrient deprivation, etc.).
  • AMPK AMP-activated protein kinase
  • AMPK regulates NADPH homeostasis to promote tumor cells survival during energy stress. Nature, 485 (2012), pp. 661-665).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • T-ALL acute T lymphoblastic leukemia
  • AMPK gene deletion caused tumor cell death and significantly Improved survival rate of mice with leukemia (Reference Eichner LJ, Brun SN. Genetic analysis reveals AMPK is required to support tumor growth in Murine Kras-Dependent Lung Cancer Models. Cell Metab. 2019 Feb 5;29(2):285-302.e7. doi: 10.1016/j.cmet.2018.10.005.).
  • HDACi is highly susceptible to drug resistance during tumor treatment. Therefore, there is a clinical need for solutions that can enhance its anti-tumor effect.
  • AMPK is one of the potential anti-tumor targets.
  • Our team found that using inhibitors to inhibit AMPK activity can enhance the anti-tumor effect of HDACi. Therefore, the combined application of AMPK inhibitors and HDACi is expected to solve the problems of clinical resistance and relapse.
  • the purpose of the present invention is to design and provide the application of AMPK inhibitor combined with HDAC inhibitor in the preparation of drugs for tumor treatment.
  • the present invention is a strategy for targeting AMPK to enhance the anti-tumor effect of HDACi, which mainly involves the combination strategy of AMPK inhibitor and HDACi and its application in anti-tumor.
  • the new method of the present invention to enhance the anti-tumor effect of HDACi mainly involves small interfering RNA and inhibitors targeting AMPK.
  • the mechanism of action is to reduce the expression of AMPK in cancer cells or inhibit AMPK signals, thereby enhancing the sensitivity of cancer cells to HDACi.
  • AMPK inhibitor combined with HDAC inhibitor in preparing drugs for treating tumor diseases.
  • the application is characterized in that the AMPK inhibitor includes Compound C.
  • the application is characterized in that the HDAC inhibitor includes HDAC inhibitor, HDACi, TMP195, TMP269.
  • the application is characterized in that the AMPK inhibitor inhibits the expression of AMPK through gene silencing/editing technology, or uses PROTAC technology to target the degradation of AMPK protein, or uses small molecule drugs to interfere with the ⁇ , ⁇ , and ⁇ subunits in AMPK.
  • the AMPK inhibitor inhibits the expression of AMPK through gene silencing/editing technology, or uses PROTAC technology to target the degradation of AMPK protein, or uses small molecule drugs to interfere with the ⁇ , ⁇ , and ⁇ subunits in AMPK.
  • the application is characterized in that the AMPK inhibitor promotes HDAC inhibitor-induced tumor cell death.
  • the application is characterized in that the tumor diseases include chronic myelogenous leukemia and cervical cancer.
  • An anti-tumor pharmaceutical composition is characterized by containing an AMPK inhibitor and an HDAC inhibitor.
  • AMPK inhibitor and HDAC inhibitor involved in the present invention can significantly promote tumor cell death and provides a new potential solution for clinical tumor treatment.
  • Figure 1 shows the combination of AMPK inhibitor (CC) and HDAC inhibitor (CC/TMP195, CC/TMP269) on K562 cell death;
  • Figure 2 shows the combination of AMPK inhibitor (CC) and HDAC inhibitor (CC/TMP195, CC/TMP269) on HeLa cell death.
  • HDAC inhibitor HDAC inhibitor, HDACi, TMP195, TMP269
  • K562 Chronic myeloid leukemia cell line
  • HeLa cervical cancer cell line
  • PI-positive cells are dead cells.
  • the AMPK inhibitor Compound C (CC) significantly promoted TMP195 HDACi-induced HeLa cell death.
  • the AMPK inhibitor Compound C (CC) significantly promoted TMP269 HDACi-induced HeLa cell death.
  • the AMPK inhibitor Compound C (CC) significantly promoted TMP195 HDACi-induced K562 cell death; as can be seen in Figure 2B, the AMPK inhibitor Compound C (CC) significantly promoted TMP269 HDACi-induced K562 cell death.

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Abstract

AMPK抑制剂与HDAC抑制剂联合在制备治疗肿瘤疾病药物中的应用及组合物。所述AMPK抑制剂包括Compound C，所述HDAC抑制剂包括TMP195和TMP269。其中AMPK抑制剂与HDAC抑制剂组合能够显著促进肿瘤细胞死亡。

Description

AMPK抑制剂联合HDAC抑制剂在制备肿瘤治疗的药物中的应用 技术领域
本发明属于抗肿瘤药物技术领域，具体涉及AMPK抑制剂联合HDAC抑制剂在制备肿瘤治疗的药物中的应用。
 背景技术
肿瘤（tumor，neoplasm）是一种非遗传的基因病。正常细胞在致瘤因素作用下，基因发生了改变，失去对其生长的正常调控，导致异常增生。肿瘤细胞有三个显著的基本特征即：不死性，迁移性和失去接触抑制。肿瘤治疗的核心思想就是杀死、清除肿瘤细胞。目前临床上常用的肿瘤治疗手段如化疗、放疗、激素治疗、分子靶向治疗、免疫治疗等。但是几乎所有的药物，随着患者使用时间的推移，癌细胞都会对药物产生抗性，使得药物对癌细胞的作用停止。肿瘤细胞对药物治疗的这种获得性抵抗力不仅严重限制了临床治疗的效果，同时也是肿瘤复发的分子基础。因此，我们需要开发新的治疗方法或优化已有的方法，一方面可以打破耐药、增强抗肿瘤效果，另一方面可以丰富我们对抗肿瘤的“武器库”，拓宽肿瘤治疗策略的选择范围。
组蛋白去乙酰化酶（Histone deacetylases，HDACs）是一个关键的基因表达调控因子，通过去除组蛋白乙酰化修饰抑制基因转录。在多数肿瘤中都观察到HDACs的异常表达，是肿瘤治疗的潜力靶点。靶向HDCA的抑制剂（HDACi）已被FDA批准用于皮肤T淋巴瘤（Cutaneous T-cell lymphoma）以及多发性骨髓瘤（Multiple myeloma）等肿瘤的治疗。尽管被寄予厚望，但临床疗效差强人意，耐药时有发生。而在实体瘤治疗方面，有多项临床实验正在开展，但截至目前，尚未有成功的案例(参考文献：Amila Suraweera, Kenneth J. O’Byrne and Derek J. Richard. Combination Therapy with Histone Deacetylase inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Frontiers in oncology. 2018 March 29: doi: 10.3389/fonc.2018.00092)。因此，临床上急需一些能够打破该药耐药性或者增强其抗实体瘤效果的方法。
腺苷酸活化蛋白激酶（AMPK）是细胞的能量和营养感受器，对细胞能量稳态以及代谢调控中起关键性作用。传统观点认为，正常情况下AMPK是一个肿瘤抑制因子，在癌症发展初期，可以通过代谢调控或者磷酸化介导肿瘤抑制因子TET2、p53、TSC2等抑制肿瘤生长。然而近年来，越来越多的研究发现在一些特殊的基因状态或代谢压力条件下（如缺氧、营养匮乏等），AMPK在肿瘤细胞中表达上调或者活化增强。对于这部分肿瘤，AMPK通过一系列保护机制帮助肿瘤细胞应对生存压力，如降低能量消耗，延缓生长，增加血管生成和抑制炎症反应等，这可能是肿瘤在恶劣条件下继续存活的重要原因之一（参考文献：Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett . 2015 Jan 28;356(2 Pt A):165-70.）。研究发现AMPK在原位移植的乳腺肿瘤中被证明是通过调节肿瘤细胞的氧化还原状态来延长细胞存活的（参考文献 S.M. Jeon, N.S. Chandel, N. Hay. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature, 485 (2012), pp. 661-665）。此外，在三种不同的小鼠白血病模型：急性髓系白血病（AML）、急性淋巴细胞白血病（ALL）、急性T淋巴细胞白血病（T-ALL）中，AMPK基因缺失导致肿瘤细胞死亡，并显著提高了小鼠白血病的存活率（参考文献 Eichner LJ, Brun SN. Genetic analysis reveals AMPK is required to support tumor growth in Murine Kras-Dependent Lung Cancer Models. Cell Metab. 2019 Feb 5;29(2):285-302.e7. doi: 10.1016/j.cmet.2018.10.005.）。也有研究发现在一个模型中，AMPK α1亚基和α2亚基的缺失使白血病细胞对由营养限制诱导的氧化还原失衡引起的细胞死亡敏感（参考文献：Saito, Y, Chapple, R.H, Lin, A, Kitano, A, and Nakada, D. AMPK protects leukemia-initiating cells in myeloid leukemias from metabolic stress in the bone marrow. Cell Stem Cell . (2015)17, 585–596.）。这些结果表明对于这部分依赖于AMPK激酶活化的肿瘤，AMPK是一个极有潜力的治疗靶点。我们的研究也证实了靶向抑制AMPK活性或者利用siRNA敲减AMPK的表达能显著诱导肿瘤细胞凋亡，抑制小鼠移植瘤的进展，证实了靶向AMPK抗肿瘤的可行性。尽管如此，AMPK抑制剂是否能够与HDACi协同增强其抗肿瘤效果，此前尚未见报道。
HDACi在肿瘤治疗过程中极容易发生耐药，因此，临床上需要能够增强其抗肿瘤效果的方案。AMPK是抗肿瘤的潜力靶点之一，本团队研究发现利用抑制剂抑制AMPK活性，能够增强HDACi的抗肿瘤效果。因此，AMPK抑制剂和HDACi的组合应用，有望解决临床耐药、复发的问题。
 技术问题
针对上述现有技术中存在的缺陷，本发明的目的在于设计提供AMPK抑制剂联合HDAC抑制剂在制备肿瘤治疗的药物中的应用。本发明一种靶向AMPK增强HDACi的抗肿瘤作用的策略，主要涉及AMPK抑制剂与HDACi的组合策略及其在抗肿瘤中的应用。
本发明增强HDACi抗肿瘤效果的新方法，主要涉及靶向AMPK的小干扰RNA、抑制剂，作用机理在于降低癌细胞AMPK的表达或者抑制AMPK信号，从而增强癌细胞对HDACi的敏感性。
 技术解决方案
AMPK抑制剂联合HDAC抑制剂在制备治疗肿瘤疾病的药物中的应用。
所述的应用，其特征在于所述AMPK抑制剂包括Compound C。
所述的应用，其特征在于所述HDAC抑制剂包括HDAC inhibitor、HDACi、TMP195、TMP269。
所述的应用，其特征在于所述AMPK抑制剂通过基因沉默/编辑技术抑制AMPK的表达，或者利用PROTAC技术靶向降解AMPK蛋白，或者利用小分子药物干扰AMPK中的 α、β、γ亚基的组合。
所述的应用，其特征在于所述AMPK抑制剂促进HDAC抑制剂诱导肿瘤细胞死亡。
所述的应用，其特征在于所述肿瘤疾病包括慢性髓性白血病、宫颈癌。
一种抗肿瘤药物组合物，其特征在于包含AMPK抑制剂和HDAC抑制剂。
 有益效果
本发明涉及的AMPK抑制剂与HDAC抑制剂组合物能够显著促进肿瘤细胞死亡，为临床肿瘤治疗提供了新的潜力方案。
 附图说明
图1为AMPK抑制剂(CC)与HDAC抑制剂的组合物(CC/TMP195, CC/TMP269)对K562细胞死亡的影响；
图2为AMPK抑制剂(CC)与HDAC抑制剂的组合物(CC/TMP195, CC/TMP269)对HeLa细胞死亡的影响。
 本发明的实施方式
以下通过具体实施例和附图对本发明作详细说明，以下实施例仅用于说明本发明，而不用于限定本发明的范围。下述实施例，中的试验方法，如无特殊说明，均为常规方法，所用实验材料均为市售产品。
实施例1：
流式细胞术检测AMPK抑制剂（Compound C,CC）与HDAC抑制剂（HDAC inhibitor, HDACi, TMP195,TMP269）组合物对肿瘤细胞死亡的影响。
1．细胞处理
1）慢性髓性白血病细胞系（K562）或宫颈癌细胞系HeLa分别以1×106细胞/孔和2×105细胞/孔的密度接种12孔板中；
2）过夜培养后，加CC（K562:20μM, HeLa: 6μM）、TMP195 (10μM)、TMP269 (10μM)或组合物（CC/TMP195或CC/TMP269, 剂量与单用组相同）培养24-36 h后，检测细胞死亡情况；
2．流式细胞术分析细胞死亡情况
1）收集细胞悬液, 将细胞悬液3200 rpm，4℃离心5 min，弃掉上清，收集沉淀中的细胞；
2）用预冷的PBS洗涤细胞1次，然后用400 μL PI染色液（0.05 mg/mL）重悬细胞；
3）4 ℃避光染色15 min；
4）式细胞仪检测凋亡情况： PI阳性的细胞为死亡细胞。
如图1所示，图1A中可看出，AMPK抑制剂Compound C（CC）显著促进了TMP195 HDACi诱导的HeLa细胞死亡。图1B中可看出，AMPK抑制剂Compound C（CC）显著促进了TMP269 HDACi诱导的HeLa细胞死亡。如图2所示，图2A中可看出，AMPK抑制剂Compound C（CC）显著促进TMP195 HDACi诱导的K562细胞死亡；图2B中可看出，AMPK抑制剂Compound C（CC）显著促进TMP269 HDACi诱导的K562细胞死亡。

Claims (7)

  1.    AMPK抑制剂联合HDAC抑制剂在制备治疗肿瘤疾病的药物中的应用。
  2.    如权利要求1所述的应用，其特征在于所述AMPK抑制剂包括Compound C。
  3.    如权利要求1所述的应用，其特征在于所述HDAC抑制剂包括HDAC inhibitor、HDACi、TMP195、TMP269。
  4.    如权利要求1所述的应用，其特征在于所述AMPK抑制剂通过基因沉默/编辑技术抑制AMPK的表达，或者利用PROTAC技术靶向降解AMPK蛋白，或者利用小分子药物干扰AMPK中的 α、β、γ亚基的组合。
  5.    如权利要求1所述的应用，其特征在于所述AMPK抑制剂促进HDAC抑制剂诱导肿瘤细胞死亡。
  6.    如权利要求1所述的应用，其特征在于所述肿瘤疾病包括慢性髓性白血病、宫颈癌。
  7.    一种抗肿瘤药物组合物，其特征在于包含AMPK抑制剂和HDAC抑制剂。
PCT/CN2022/137379 2022-04-22 2022-12-07 Ampk抑制剂联合hdac抑制剂在制备肿瘤治疗的药物中的应用 Ceased WO2023202091A1 (zh)

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