药学学报

Generic name	Corporation	Chemical classification	Target	Indication
Vorinostat	Merck	Lvalonic acid	Pan	Advanced, persistent, or recurrent T-cell lymphoma with two previous systemic treatments^[13]
Panobinostat	Novartis	Lvalonic acid	Pan	Multiple myeloma with at least two prior treatments^[14]
Belinostat	Spectrum	Lvalonic acid	Pan	Recurrent or refractory peripheral T-cell lymphoma^[15]
Romidepsin	Celgene	Cyclic peptide	HDAC1, 2	Cutaneous T-cell lymphoma with at least one systemic treatment^[16]
Chidamide	Chipscreen Biosceinces	Benzamide	HDAC1, 2, 3, 10	Recurrent or refractory peripheral T-cell lymphoma with at least one prior systemic chemotherapy

Generic name	Corporation	Chemical classification	Target	Indication
Vorinostat	Merck	Lvalonic acid	Pan	Advanced, persistent, or recurrent T-cell lymphoma with two previous systemic treatments^[13]
Panobinostat	Novartis	Lvalonic acid	Pan	Multiple myeloma with at least two prior treatments^[14]
Belinostat	Spectrum	Lvalonic acid	Pan	Recurrent or refractory peripheral T-cell lymphoma^[15]
Romidepsin	Celgene	Cyclic peptide	HDAC1, 2	Cutaneous T-cell lymphoma with at least one systemic treatment^[16]
Chidamide	Chipscreen Biosceinces	Benzamide	HDAC1, 2, 3, 10	Recurrent or refractory peripheral T-cell lymphoma with at least one prior systemic chemotherapy

Generic name	Corporation	Target	Indication
Idelalisib	Gilead	PI3Kδ	1. Monotherapy for relapsed chronic lymphocytic leukemia and follicular B-cell non-Hodgkin's lymphoma 2. Small cell lymphoma^[46]
Copanlisib	Bayer	PI3Kα, PI3Kδ	Small cell lymphoma^{[47, 48]}
Duvelisib	Verastem	PI3Kδ, PI3Kγ	Relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma/follicular lymphoma^{[49, 50]}
Alpelisib	Novartis	PI3Kα	In combination with flulvesant for advanced or metastatic breast cancer with PIK3CA mutation^[51]
Umbralisib	TG Therapeutics	PI3Kδ	Recurrent or refractory marginal zone lymphoma/follicular lymphoma

Generic name	Corporation	Target	Indication
Idelalisib	Gilead	PI3Kδ	1. Monotherapy for relapsed chronic lymphocytic leukemia and follicular B-cell non-Hodgkin's lymphoma 2. Small cell lymphoma^[46]
Copanlisib	Bayer	PI3Kα, PI3Kδ	Small cell lymphoma^{[47, 48]}
Duvelisib	Verastem	PI3Kδ, PI3Kγ	Relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma/follicular lymphoma^{[49, 50]}
Alpelisib	Novartis	PI3Kα	In combination with flulvesant for advanced or metastatic breast cancer with PIK3CA mutation^[51]
Umbralisib	TG Therapeutics	PI3Kδ	Recurrent or refractory marginal zone lymphoma/follicular lymphoma

HDAC抑制剂及其联合PI3K抑制剂抗肿瘤研究进展

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黄蕾 , 陈晓光 ^* , 来芳芳 ^*

药学学报 | 综述 2022,57(12): 3557-3563

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药学学报 | 综述 2022, 57(12): 3557-3563

HDAC抑制剂及其联合PI3K抑制剂抗肿瘤研究进展

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黄蕾, 陈晓光^*, 来芳芳^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

通讯作者:

*陈晓光, E-mail: chxg@imm.ac.cn;

来芳芳, Tel: 86-10-63165207, E-mail: laifangfang@imm.ac.cn

Advances in anti-tumor research of HDAC inhibitors and combination with PI3K inhibitors

Lei HUANG, Xiao-guang CHEN^*, Fang-fang LAI^*

Affiliations

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2022-12-12 doi: 10.16438/j.0513-4870.2022-0672

文章导航

摘要

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组蛋白去乙酰化酶(histone deacetylase, HDAC) 通常异常过表达, 导致肿瘤抑制基因的转录抑制。作为具有巨大潜力的抗癌药物, 组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDIs) 可以通过调节核小体结构, 抑制HDAC活性, 调控抑癌基因表达而发挥抗肿瘤效应。目前, 已上市的5个HDAC抑制剂适应症局限于外周T细胞淋巴瘤和皮肤T细胞淋巴瘤, 而在实体瘤方面, 大多数作为单一药物使用的HDAC抑制剂未能得到有效的治疗效果。磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K) 是PI3K-AKT-mTOR信号通路的起始节点, 在肿瘤细胞的增殖、迁移、侵袭、分化等过程中起着十分重要的作用, 该通路的异常激活与肿瘤的发生发展有着密切关系, 将HDAC抑制剂和PI3K抑制剂的联合使用以及HDAC/PI3K双靶点抑制剂能够改善单独用药时存在的问题。本综述介绍了具有代表性的HDIs和PI3K抑制剂, 以及HDAC/PI3K抑制剂联用及双靶点抑制剂的抗肿瘤临床和临床前研究进展。

关键词

HDAC抑制剂 / PI3K抑制剂 / 联合用药 / HDAC/PI3K双靶点抑制剂 / 抗肿瘤

Abstract

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Histone deacetylase (HDAC) is usually abnormally overexpressed, which mainly leads to the transcriptional repression of tumor suppressor genes. Histone deacetylase inhibitors (HDIs) exert anti-tumor biological effects by regulating nucleosome structure, inhibiting HDAC activity, and controlling the expression of tumor suppressor genes. There are currently 5 drugs on the market, but only for peripheral T-cell lymphoma and cutaneous T-cell lymphoma. In solid tumors, most of the HDAC inhibitors used have failed to achieve effective therapeutic effects. Phosphoinositide 3-kinase (PI3K) is the starting node of the PI3K-AKT-mTOR signaling pathway, which plays a very important role in the proliferation, migration, invasion, and differentiation of tumor cells. The abnormal activation of PI3K is closely related to the occurrence and development of tumors, and the combined use of HDAC and PI3K inhibitors and HDAC/PI3K dual-target inhibitors show synergistic anticancer activity. This article introduces the anti-tumor clinical and preclinical research progress of representative HDAC inhibitors and PI3K inhibitors, as well as HDAC/PI3K dual-target inhibitors.

Key words

HDAC inhibitor / PI3K inhibitor / combination therapy / HDAC/PI3K dual-target inhibitor / anti-tumor

引用本文

黄蕾, 陈晓光, 来芳芳. HDAC抑制剂及其联合PI3K抑制剂抗肿瘤研究进展. 药学学报, 2022 , 57 (12) : 3557 -3563 . DOI: 10.16438/j.0513-4870.2022-0672

Lei HUANG, Xiao-guang CHEN, Fang-fang LAI. Advances in anti-tumor research of HDAC inhibitors and combination with PI3K inhibitors[J]. Acta Pharmaceutica Sinica, 2022 , 57 (12) : 3557 -3563 . DOI: 10.16438/j.0513-4870.2022-0672

正文

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肿瘤是一种发病机制和病理进展极其复杂的恶性疾病, 与许多基因相关, 包含多个复杂的病理环节。癌症化疗是近几十年来医学上的重大进步之一。然而用于这种治疗的药物治疗窗狭窄, 并且产生的反应通常是不可预测的。相比之下, 近年来针对癌症特异性靶点和信号通路, 引入的靶向治疗有着巨大的研究潜力。研究表明, 表观遗传机制在癌症发展中起着至关重要的作用。其中蛋白质中的赖氨酸乙酰化是真核细胞中最丰富的翻译后修饰之一, 赖氨酸乙酰化和去乙酰化的动态稳态是由组蛋白乙酰转移酶(histone acetyltransferases, HATs) 和组蛋白去乙酰化酶(histone deacetylases, HDACs) 的作用共同决定的, HDACs是组蛋白修饰过程中一类重要的酶, 催化并调控组蛋白去乙酰化。

1 HDAC抑制剂抗肿瘤

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人类基因组中共有18个HDACs, 这些酶可以分为锌依赖型和烟酰胺腺嘌呤二核苷酸(NAD⁺) 依赖型, 也被称为sirtuins (III类)。依赖锌的HDACs可进一步分为I类(HDAC1、HDAC2、HDAC3和HDAC8)、IIA类(HDAC4、HDAC5、HDAC7和HDAC9)、IIb类(HDAC6和HDAC10) 和IV类(HDAC11)^{[1, 2]}。

异常HDACs在许多人类疾病中起关键作用, 包括但不限于癌症、神经系统疾病、代谢障碍^{[3, 4]}。HDACs在血液瘤和实体瘤中异常表达, 在胃癌和激素难治性前列腺癌中HDAC1水平升高^{[5, 6]}, 在结肠癌中HDAC2和HDAC3高表达^[7], 在乳腺癌中HDAC4由于突变而表达降低^{[1, 8]}。除组蛋白外, HDACs还能够去乙酰化其他蛋白, 这可能会导致细胞毒性。目前, HDACs已被确定为一种治疗癌症和相关疾病的显著药物靶点。HDAC抑制剂(histone deacetylase inhibitors, HDIs) 能够抑制多种HDAC的活性, 导致组蛋白恢复乙酰化水平, 调节相关信号通路^[9], 诱导特定基因的表达, 从而引发广泛的细胞形态和代谢变化, 如生长停滞、衰老、分化和凋亡^{[10, 11]}。

HDIs从结构上可分为异羟戊酸、环状肽、苯甲酰胺和脂肪酸4类。迄今为止, 全球已经有5种HDIs获得批准上市, 分别是vorinostat、panobinostat、belinostat、romidepsin和chidamide^[12] (表 1^[13-16])。

2 HDAC抑制剂抗肿瘤机制

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2.1 调节基因转录

研究发现, 组蛋白乙酰化能够使沉默的肿瘤抑制基因再表达^{[17, 18]}。负责调节细胞周期、凋亡、DNA修复基因的启动子区域往往被高度甲基化, 从而在肿瘤中沉默, 但DNA甲基化状态影响局部组蛋白乙酰化水平^[19]。靶向这些沉默基因使之再表达则能够达到很好的抗肿瘤效果。有研究表明, 组蛋白乙酰化会导致核小体构象发生变化, 并使转录因子更容易接近DNA。如IIa类HDIs C末端结构域能够直接与类视黄醇和甲状腺激素受体的沉默介体(silencing mediator for retinoid and thyroid hormone receptors, SMRT) 及核受体辅阻遏物(nuclear receptor corepressor, N-CoR) 相互作用, 从而减少SMRT和N-CoR与未结合的核受体及其他转录因子相互作用^{[20, 21]}。

2.2 调节蛋白质降解

除组蛋白外, HDACs也能够翻译后修饰其他蛋白质, 导致其功能、稳定性或细胞定位改变^[22]。错误折叠的蛋白质不仅会干扰正常细胞功能, 而且还是许多神经退行疾病中神经元细胞死亡的主要促成因素^{[23, 24]}。HDAC6可以通过去乙酰化热休克蛋白90 (heat-shock protein, HSP90) 在错误折叠的蛋白质反应中起关键作用, 稳定肿瘤细胞生长所依赖蛋白的受体表达, 如融合基因Bcr-Abl、FMS络氨酸激酶3 (Fms-like tyrosine kinase-3, FLT3) 等^[25], 而HDIs能够通过抑制HDAC6阻止复合物解聚, 导致内质网应激反应, 从而促进癌蛋白降解^[26]。

2.3 诱导细胞凋亡

诱导细胞凋亡是HDIs促进抗癌作用的主要机制之一^{[27, 28]}。研究发现, HDIs通过上调细胞表面死亡受体和配体表达, 降低细胞质FLICE样抑制蛋白(c-FLICE inhibitory protein, c-FLIP) 水平和增强死亡诱导信号复合物(death-inducing signaling complex, DISC) 等外源性凋亡途径来增强信号传导^[29]。重要的是, HDIs对外源性凋亡途径的作用还可以增强许多肿瘤细胞对该途径的激活剂如死亡配体-受体1 (the related apoptosis inducing ligand 1, TRAIL-1) 的敏感性^[30]。并且HDIs也能增加内源性促凋亡反应, 增强Bax等促凋亡蛋白或降低Bcl等抗凋亡蛋白的表达^{[31, 32]}。HDIs影响凋亡信号的一个重要机制是产生活性氧(reactive oxygen species, ROS), 使得线粒体膜电位损失和细胞色素c释放, 最终导致半胱天冬酶级联的激活, 表现为多聚(ADP-核糖) 聚合酶[poly (ADP-ribose) polymerase, PARP]、p21 (CIP1/WAF1)、p27 (KIP) 和Bcl-2蛋白降解^[33]。

一系列的HDIs, 如vorinostat、rromidepsin、panobinostat已证明在治疗难治性皮肤T细胞淋巴瘤、外周T细胞淋巴瘤和多发性骨髓瘤方面取得了临床成功^[34]。但是在实体瘤方面, 尽管在体外和临床前模型方面取得一些进展, 如西达本胺, 作为全球首个批准上市的亚型选择性组蛋白去乙酰化酶口服抑制剂用于治疗外周T细胞淋巴瘤, 在2019年, 获得中国国家药品监督管理局(National Medical Products Administration, NMPA)正式批准, 联合芳香化酶抑制剂用于治疗激素受体阳性、人表皮生长因子受体-2阴性、绝经后、经内分泌治疗复发或进展的局部晚期或转移性乳腺癌患者, 但是大多数已知的作为单一药物使用的HDIs在实体瘤方面尚未能得到有效的治疗效果^[35-37]。

HDIs在实体瘤中反应不佳的原因仍不清楚, 有可能是因为药物诱导的恶性细胞和肿瘤微环境的代偿性改变而导致缺乏反应。鉴于HDIs对恶性细胞的多效作用, 其真正的治疗潜力很可能在于与其他抗癌药物的结合^[38]。将HDIs与其他抗肿瘤药物联合使用可以起到一定的协同作用, 减少毒副作用的同时, 运用机制上的互补性还能提高疗效、扩展适应症, 因此, 联合用药将为HDIs拓展更广阔的市场空间^[39]。

3 PI3K抑制剂单独用药抗肿瘤

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磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K) 是一个脂质激酶家族, 参与调节多种信号通路, 如细胞增殖、生长、运动和代谢^{[40, 41]}。PI3K过度激活经常发生在多种癌症中, 几乎介导近50%的恶性肿瘤的发生, 使得这类酶成为一种很有前景的抗癌治疗的靶点^{[42, 43]}。PI3K是由催化亚基和调节亚基组成的复合物, 根据结构和底物的特异性不同, 可分为Ⅰ、Ⅱ、Ⅲ型, 其中Ⅰ型是目前研究最深入、最广泛的亚型, 与肿瘤关系也最为密切。Ⅰ型又可分为ⅠA和ⅠB类, 其中, ⅠA类包括3种亚型, 分别为PI3Kα、PI3Kβ、PI3Kδ, 而ⅠB类为PI3Kγ^{[42, 44]}。在肿瘤的发生发展过程中, 负责编码PI3Kα的基因PIK3CA突变后, 异常激活PI3Kα的同时, 还能抑制抑癌基因PTEN (phosphatase and tension holomogue deleted on chromosome ten) 的表达从而能够促进细胞周期进展、维持细胞存活、调控细胞生长、促进血管生成等^[45]。根据药物代谢动力学特性和对ATP结合位点的异构体选择性, PI3K抑制剂可分为PI3K/mTOR双重抑制剂、泛PI3K抑制剂、PI3K亚型特异性抑制剂^[10]。目前, 全球范围内共有5款PI3K抑制剂上市, 分别为copanlisib、alpelisib、idelalisib、duvelisib及umbralisib (表 2)^[46-51]。

4 HDAC抑制剂联用PI3K抑制抗肿瘤

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在临床试验的早期阶段, 由于缺乏选择性、信号循环差、表观遗传变化及激活其他肿瘤细胞生长生存通路等, 导致PI3K抑制剂抗肿瘤效果有限^[52]。而联合HDIs是提高PI3K通路抑制剂有效性的一种方法。目前, HDIs与PI3K抑制剂的协同策略在临床前和临床研究中都表现出潜在的抗肿瘤作用^{[11, 53, 54]}。这是因为HDIs可以使AKT不稳定, 增加氧化应激, 并能够克服对PI3K-AKT-mTOR途径的耐药性^[55]。而PI3K抑制剂的加入也可以改善HDIs由于瞬时诱导EGFR/AKT信号的激活导致对肿瘤细胞敏感性降低的问题。此外, PI3K抑制剂还能够加强HDIs诱导肿瘤细胞凋亡的能力^[56]。近年来, HDAC/PI3K抑制剂联用引起了广泛关注^[57]。

Yoshioka等^[58]将新型HDIs OBP-801/YM753和PI3K抑制剂LY294002联用, 来探索对人子宫内膜癌细胞系HEC-1A的作用机制。经研究发现, OBP-801/YM753和LY294002的联用与单独用药相比, 能够显著抑制HEC-1A生长, 并通过诱导凋亡调节蛋白Bim (Bcl-2 interacting mediator of cell death) 表达和ROS积累促进HEC-1A凋亡。此外, 在体内动物实验中, OBP-801/YM753和LY294002联合治疗显著抑制肿瘤生长, 效果强于单药使用。这种联合应用有望成为子宫内膜癌的一种新治疗策略。

而Ozaki等^[59]也发现单独使用LY294002只能通过阻断PI3K-AKT途径诱导肿瘤细胞低水平死亡, 但是当联合HDIs HC Toxin时, LY294002可以显著提高HC Toxin对累积ROS的敏感, 增强HC Toxin的细胞毒性, 从而诱导非小细胞肺癌或慢性粒细胞白血病细胞凋亡。

Wang^[60]等为确定PI3K抑制是否可以增强HDIs NaBT对侵袭性人结肠癌细胞系KM20和HCT116的抑制作用, 将PI3K抑制剂wortmannin及LY294002与NaBT联用, 发现与单独用药相比, 联用wortmannin或LY294002能够增强半胱天冬酶-9和半胱天冬酶-3的激活及随后的PARP裂解, 从而增强NaBT诱导的人结肠癌细胞系KM20和HCT116的凋亡。在体内动物实验上, wortmannin和NaBT的组合能够完全抑制KM20肿瘤异种移植物的生长, 效果强于单独用药。

Zhou等^[56]研究发现组蛋白乙酰化的改变对卵巢癌细胞的增殖和迁移有显著影响。用TSA处理卵巢癌细胞系Caov3 24 h后, Caov3的存活和增殖及细胞迁移受到显著抑制。然而TSA能够瞬时诱导EGFR/AKT信号的激活, 导致生存素的表达, 从而使Caov3对TSA的敏感性降低。当联合LY294002后, 抑制TSA瞬时激活的EGFR/AKT不仅阻断TSA诱导的生存素表达, 而且增强TSA诱导的组蛋白H4乙酰化, 从而促进细胞死亡并抑制细胞迁移。这表明EGFR/AKT信号可能是提高TSA治疗卵巢癌疗效的新靶点。

Rahmani等^[61]为研究PI3K/AKT通路失调对人类白血病细胞对HDIs反应的影响, 将LY294002和HDIs丁酸钠(sodium butyrate, SB) 共同作用于人组织淋巴瘤细胞U937细胞24 h后, 发现能够导致U937线粒体损伤、半胱天冬酶激活及细胞凋亡显著增加。此外, 该团队还发现联合用药处理细胞后, LY294002通过使丝裂原活化蛋白酶激酶(mitogen-activated protein kinase, MAPK) 失活和干扰p21 (CIP1/WAF1) 诱导的AKT非依赖性过程促进SB介导的细胞凋亡。这表明PI3K激酶下游靶点的阻断也可以增强HDIs介导的肿瘤细胞杀伤能力。

5 HDAC/PI3K双靶点抑制剂

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联合用药会导致药物之间的相互作用, 无法预测不良反应和复杂的药动学特征等问题^[62]。相比于单靶点药物, 多靶点药物可以在相对较低的血药浓度水平达到单靶点药物在高浓度水平才能产生的生物学效应, 减轻药物的不良反应。此外, 多靶点药物可以通过抑制肿瘤细胞内的多个不同通路的靶标来消除旁路代偿机制, 从而防止产生耐药性, 达到一加一大于二的效果, 提高药物的疗效, 因此越来越多的研究者聚焦于HDAC/PI3K双靶点抑制剂的开发。

5.1 FK-228及其类似物

在HDAC/PI3K双靶点抑制剂研究中, 最早发现的是FK-228。它是环状肽类HDIs, 但是同时也可以有效地抑制AKT磷酸化, 抑制PI3K-AKT通路。尽管FK-228只能在微摩尔范围内抑制PI3K^[63], 但是这也表明HDAC和PI3K抑制之间可能存在协同作用。FK-228的结构类似物FK-A11在较低浓度下抑制AKT的磷酸化并加速组蛋白乙酰化, 在肿瘤细胞中产生比FK228和其他类似物更强的细胞毒性作用^[64]。

5.2 BEBT-908

BEBT-908是一款同时靶向HDAC和PI3Kα的双靶点抑制剂, 能够选择性抑制具有协同作用的肿瘤细胞信使的核心靶点, 破坏肿瘤细胞信使, 显著抑制淋巴瘤和骨髓瘤生长, 导致肿瘤消退^[65]。目前研究表明, BEBT-908能够通过促进细胞铁死亡来有效抑制肿瘤生长, 并且加强了免疫检查点抑制疗法的作用^[66]。BEBT-908正处于II期临床试验阶段, 对弥漫性大B细胞淋巴瘤、复发难治性淋巴瘤、多发性骨髓瘤和慢性淋巴细胞白血病等临床研究已经获批。2021年9月, BEBT-908拟纳入突破性疗法, 用于三线治疗复发或难治性弥漫性大B细胞淋巴瘤。

5.3 CUDC-907

CUDC-907是一种口服小分子, 在保留PI3K抑制剂apitolisib的关键活性基团吗啉-嘧啶并噻吩结构的同时, 引入HDIs的ZBG (异羟肟酸) 基团^[65]。CUDC‐907能够多重抑制HDAC I类、II类和IV类(HDAC1、2、3、6、10和11) 和PI3KI类(PI3KIα、β和δ)^[67]。CUDC‐907已在实体瘤和血液系统恶性肿瘤的多个临床前模型中取得显著的抗肿瘤活性。CUDC-907的突出特点是下调MYC并抑制MYC依赖的肿瘤的生长, 伴C-MYC易位者疗效明显优于不伴C-MYC易位者。除此之外, CUDC-907能够抑制肿瘤相关的成纤维细胞活化, 降低肺和肿瘤纤维化^[68]。CUDC-907于2015年在美国被指定为用于治疗复发或难治性弥漫性大B细胞淋巴瘤的孤儿药。目前, CUDC-907用于治疗难治或复发性弥漫性大B细胞淋巴瘤和有无MYC或BCL2变化的高级别大B淋巴瘤处于I期临床试验; 治疗三阴乳腺癌、高级别严重性卵巢癌和中线癌处于I期临床试验; 治疗未分化和低分化甲状腺肿瘤处于II期临床试验。

5.4 先导化合物

此外, 现在还有大量靶向抑制HDAC/PI3K双靶点的先导化合物处于临床前研究, Chen等^[69]在羟肟酸的基团上进行改造, 将吗啉嘌呤作为帽基的核心结构支架, 制备了一系列羟肟酸类似物, 并评价了体内外的生物活性。其中活性较好的双靶标抑制剂有10s和10o, 10s能够有效抑制PI3Kα和HDAC各亚型的活性, 但水溶性差, 毒性大; 10o对HDAC I类和IIb类亚型的活性优于其他亚型。在人白血病细胞MV4-11和HCT116异种移植模型中, 10o的抗肿瘤活性明显优于阳性对照组SAHA, 在人骨髓瘤细胞系MM1S异种移植模型中, 抗肿瘤活性优于panobinostat。

Chen等^[70]设计开发了一系列嘌呤或5H-pyrrolo [3, 2-d] 嘧啶羟胺盐作为多靶点药物来调节HDACs和PI3K/AKT/mTOR通路。在筛选的39个细胞系中, 发现化合物20e、20f和20q对白血病、淋巴瘤和原发性肝癌细胞的选择性最高, 其中, 化合物20f在高血管性肝癌模型中有着显著的单药口服疗效, 且耐受性良好, 说明20f值得进一步发展。

Yan等^[71]发现取代PI3K支架上甲氧基吡啶的3-位置可以控制PI3K, 而羟肟酸连接体的变化可以有效控制HDAC活性, 从而为实现PI3K和HDAC活性的最佳组合提供了一个有效的策略。研究者分别选择具有烷基连接子和嘧啶连接子的化合物23和36做进一步分析, 构效关系研究表明, 化合物23和36能够同时抑制PI3K和HDAC, 并有良好的抗增殖活性。相对于阳性药PI3K抑制剂BKM120或HDIs SAHA, 化合物23对97个激酶靶点具有较高的选择性, 显著抑制血液肿瘤增殖。此外, 化合物23和36也能诱导肿瘤细胞周期阻滞在G1期, 诱导细胞凋亡, 在HCT116异种移植模型中进一步评估, 均显示出显著的体内抗癌效果。但是与其他基于羟肟酸的HDAC抑制剂类似, 23和36在药代动力学研究中表现出快速清除和较差的口服生物利用度^[54]。

6 小结与展望

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PI3K和HDAC是近些年来比较热门的抗肿瘤靶点, 本综述介绍了HDAC、PI3K在肿瘤发生发展的作用和HDAC/PI3K抑制剂联用及双靶点抑制剂的研究进展。PI3K抑制剂和HDAC抑制剂单独用药抗肿瘤存在固有缺陷, 如产生耐药性、减弱疗效、易产生毒副作用等。此外, 由于机体存在复杂的自我调节功能, 长期使用可能会激活旁路代偿机制, 从而使疾病对该种药物的敏感度下降, 产生耐药性^[72]。

将HDIs和PI3K抑制剂联用后, 可以改善HDIs由于瞬时诱导EGFR/AKT信号的激活导致对肿瘤细胞敏感性降低的问题, 促进肿瘤细胞凋亡, 同时也可以克服PI3K抑制剂耐药性^[56]。但是联合用药又会导致药物之间的相互作用, 无法预测不良反应和复杂的药动学特征等问题^[62]。

相对而言, 针对多靶点的抗肿瘤药物能够作用于不同病理环节和不同发病机制, 产生协同抗癌作用, 达到一加一大于二的效果, 提高药物的疗效, 在相对较低的血药浓度水平达到单靶点药物在高浓度水平才能产生的生物学效应, 减轻药物的不良反应。并且多靶点药物可以通过抑制肿瘤细胞内的多个不同通路的靶标来消除旁路代偿机制, 从而防止产生耐药性。因此, 越来越多研究人员开始聚焦于HDAC/PI3K双靶点药物的研发^[73]。

迄今为止, HDAC/PI3K双靶点抑制剂上市药物只有CUDC-907, 大部分仍处于临床前研究, 但是相信随着医学研究的发展, HDAC/PI3K双靶点抑制剂在肿瘤临床治疗上一定会发挥更大的作用。当然, 药物组合的理想叠加或协同效应有可能会导致有害的药物相互作用和脱靶活性, 从而产生不良反应, 最终损害患者的依从性, 这也是双靶点研究过程中的一个重大挑战^[74]。

作者贡献: 黄蕾撰写了全文, 对内容进行修改和补充; 陈晓光和来芳芳对文章进行审阅并提出合理的修改意见。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金面上项目(82173854)

参考文献

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文献

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2022年第57卷第12期

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doi: 10.16438/j.0513-4870.2022-0672

接收时间：2022-05-29
首发时间：2025-12-24
出版时间：2022-12-12

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收稿日期：2022-05-29
修回日期：2022-07-10

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国家自然科学基金面上项目(82173854)

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中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

通讯作者:

*陈晓光, E-mail: chxg@imm.ac.cn;

来芳芳, Tel: 86-10-63165207, E-mail: laifangfang@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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