小分子Bcl-2抑制剂的研究与开发

综述细胞凋亡的主要机制、Bcl-xL蛋白结构以及各类小分子Bcl-2抑制剂的研究与开发。高水平表达Bcl-2家族抗凋亡蛋白（如Bcl-2、Bcl-xL等）可导致肿瘤细胞的凋亡过程受阻，并对传统放、化疗产生抵抗性，而下调过表达Bcl-2和Bcl-xL蛋白则可诱导肿瘤细胞凋亡，且逆转肿瘤细胞对治疗的抵抗性或耐药性。因此，作为潜在的癌症治疗策略，以Bcl-2家族蛋白为靶点的小分子抑制剂已成为当今研究热点，X-射线晶体衍射、核磁共振技术、小分子数据库和计算机辅助药物设计等技术也广泛应用于小分子Bcl-2抑制剂的开发。     

Bcl-2家族蛋白小分子抑制剂的研究进展

Bcl-2家族蛋白是细胞凋亡途径中一种重要的蛋白,在肿瘤的发生及转移中起着重要的作用.由于Bcl-2家族蛋白在多种癌细胞中高度表达,因此,对其干预成为一种新型肿瘤治疗策略,Bcl-2家族蛋白也成为抗肿瘤的热门靶点之一.本文总结了近年来Bcl-2家族蛋白小分子抑制剂的研究进展.     

Bcl-2蛋白的小分子抑制剂

Bcl-2蛋白家族在调节细胞凋亡中发挥重要作用，人类恶性肿瘤细胞高表达Bcl-2和Bcl-XL，而高表达这些抗凋亡分子的细胞对于化疗药物有抗性，因此，以Bcl-2家族蛋白为靶点的小分子抑制剂成为很有潜力的可用于多种肿瘤治疗的药物，通过下调Bcl-2和Bcl-XL的表达直接影响肿瘤细胞的存活及其对化疗药物的抗性。     

Bcl-2蛋白家族作用机制及其抑制剂的研究

综述了Bcl-2蛋白家族成员的结构、作用机制模式及抑制剂，特别是小分子抑制剂的研究进展。凋亡对于调节多细胞生物的个体发育和体内平衡具有重要作用，其异常可导致许多疾病的发生，而Bcl-2蛋白家族在凋亡通路中起重要的调节作用，它们与肿瘤的产生及耐药非常相关，可能成为抗肿瘤药物的新靶点。近几年研究者对它们的抑制剂也进行了初步研究。     

基于Bcl-2蛋白关键位点抑制剂的研究

目的 设计并合成高抑制活性的小分子Bcl-2蛋白抑制剂.方法 基于已报道的活性小分子,运用Autodock 4.2软件研究其与Bcl-2蛋白的作用模式,探索Bcl-2蛋白的关键位点并设计、合成一系列新型小分子抑制剂,并进行体外抗肿瘤活性的实验.结果 设计合成了8个全新的小分子化合物,其结构经1HNMR和13CNMR确证.结论 所合成的8个化合物均有明显的体外抗肿瘤活性,且大部分高于阳性对照紫杉醇.     

基于Bcl-2蛋白P2、P3活性区域抑制剂的设计、合成及体外活性研究

目的 探索Bcl-2蛋白P2、P3活性区域的构效关系,并设计合成活性较好的抑制剂.方法 基于对Bcl-2蛋白抑制剂、Bcl-2蛋白P2、P3活性区域的分析,利用Autodock 4.2软件设计对接,合成一系列新型Bcl-2小分子抑制剂;采用MTT法测定所合成的抑制剂对人恶性黑色素瘤细胞A375、人肝癌细胞HepG-2、人非小细胞肺癌细胞A549的体外抗肿瘤活性.结果 合成了13个新型Bcl-2小分子抑制剂(D1～ D13),其中,化合物D2、D6、D8的活性相对较好,对人恶性黑色素瘤细胞A375的抑制作用与阳性对照紫杉醇相当;化合物D1、D3、D4、D5也对A375细胞具一定的抑制活性.结论 获得了P2、P3活性区域的构效关系,有助于Bcl-2蛋白抑制剂的进一步研究.     

新型小分子Bcl-2蛋白抑制剂的设计、合成及体外活性研究

目的 设计并合成新型小分子Bcl-2蛋白抑制剂.方法 基于已报道的活性小分子,运用Autodock4.2研究其与Bcl-2蛋白的作用模式,并以此设计、合成一系列新型小分子抑制剂,采用MTT法对人肝癌细胞HepG-2进行体外抗肿瘤活性实验.结果 设计合成了11个全新小分子化合物,其结构经1HNMR和13CNMR确定.结论 化合物Ⅱ、Ⅴ、Ⅹ、Ⅺ有明显的体外抗肿瘤活性,化合物Ⅵ显示出比较好的体外抗肿瘤活性,高于阳性对照.     

Mcl-1小分子抑制剂研究进展

MCL-1(myeloid cell leukemia-1)蛋白是BCL-2(B-cell lymphoma-2)蛋白家族中重要的抗凋亡蛋白成员之一,在多种肿瘤细胞中过表达。Mcl-1蛋白的过表达不仅与肿瘤的发生发展密切相关,还会导致肿瘤细胞对化疗药物产生耐药性,因此以Mcl-1为靶点的小分子抑制剂是未来抗肿瘤药物研发的重点。本文对2012-2017年间发表的Mcl-1小分子抑制剂进行了综述,主要介绍小分子抑制剂的化学结构和生物活性,旨在为Mcl-1小分子抑制剂的深入研究以及更多海洋来源的新型Mcl-1小分子抑制剂的开发提供参考。     

维奈克拉联合用药治疗急性髓系白血病的研究进展

Bcl-2是调控肿瘤细胞凋亡的关键分子,也是近年研究证实的白血病治疗新靶点.针对该靶点的Bcl-2抑制剂维奈克拉与去甲基化药物的联合用药方案于2018年11月获美国食品和药物管理局批准,用于治疗75岁及以上初治或有合并症不适合高强度化疗的急性髓系白血病(AML)患者.多项研究证实维奈克拉联合去甲基化药物或小分子抑制剂在...     

干扰 p53-MDM2 蛋白相互作用的小分子抑制剂的研究进展

p53-MDM2 蛋白相互作用是抗肿瘤药物研究的重要作用靶点,抑制 p53-MDM2 结合是激活p53 的有效途径。大量的药物筛选方法和手段已经用于寻找 p53-MDM2 相互作用的新型抑制剂,其中小分子抑制剂是最具前景的研究领域之一。该文总结了近年来国内外p53-MDM2 蛋白结合小分子抑制剂的研究进展。     

Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review

INTRODUCTION: The B-cell lymphoma-2 (Bcl-2) family of proteins is central to the regulation of apoptosis, which is vital for proper tissue development and cellular homeostasis. Anti-apoptotic proteins, members of the Bcl-2 family, are an important survival factor for many cancers and their overexpression has been associated with tumor initiation, progression, and resistance to current anticancer therapies. Therefore, strategies seeking to antagonize the function of Bcl-2 anti-apoptotic proteins have been extensively studied for developing a novel cancer therapy. AREAS COVERED: This review covers research and patent literature of the last 15 years dealing with the discovery and development of inhibitors of the Bcl-2 protein family. EXPERT OPINION: The feasibility of disrupting protein-protein interactions between anti-apoptotic and pro-apoptotic proteins, members of the Bcl-2 family, using peptidomimetics and small-molecule inhibitors has been successfully established. Three small-molecule inhibitors have entered human clinical trials, which will allow the evaluation of this potential therapeutic approach in cancer patients. It will be important to gain a better understanding of pan and selective Bcl-2 inhibitors in order to facilitate future drug design efforts.     

Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins

We report herein a new class of small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound, 7, binds to Bcl-2, Bcl-xL, and Mcl-1 proteins with Ki of 110, 638, and 150 nM, respectively. Compound 7 is highly effective in induction of cell death in breast cancer cells with high levels of Bcl-2, Bcl-xL, and Mcl-1 proteins and represents a promising lead compound for the design of new anticancer drugs.     

Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening.

Bcl-2 belongs to a growing family of proteins which regulates programmed cell death (apoptosis). Overexpression of Bcl-2 has been observed in 70% of breast cancer, 30-60% of prostate cancer, 80% of B-cell lymphomas, 90% of colorectal adenocarcinomas, and many other forms of cancer. Thereby, Bcl-2 is an attractive new anti-cancer target. Herein, we describe the discovery of novel classes of small-molecule inhibitors targeted at the BH3 binding pocket in Bcl-2. The three-dimensional (3D) structure of Bcl-2 has been modeled on the basis of a high-resolution NMR solution structure of Bcl-X(L), which shares a high sequence homology with Bcl-2. A structure-based computer screening approach has been employed to search the National Cancer Institute 3D database of 206 876 organic compounds to identify potential Bcl-2 small-molecule inhibitors that bind to the BH3 binding site of Bcl-2. These potential Bcl-2 small-molecule inhibitors were first tested in an in vitro binding assay for their potency in inhibition of the binding of a Bak BH3 peptide to Bcl-2. Thirty-five potential inhibitors were tested in this binding assay, and seven of them were found to have a binding affinity (IC(50) value) from 1.6 to 14.0 microM. The anti-proliferative activity of these seven active compounds has been tested using a human myeloid leukemia cell line, HL-60, which expresses the highest level of Bcl-2 protein among all the cancer cell lines examined. Compound 6 was the most potent compound and had an IC(50) value of 4 microM in inhibition of cell growth using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Five other compounds had moderate activity in inhibition of cell growth. Compound 6 was further evaluated for its ability to induce apoptosis in cancer cells. It was found that 6 induces apoptosis in cancer cells with high Bcl-2 expression and its potency correlates with the Bcl-2 expression level in cancer cells. Furthermore, using NMR methods, we conclusively demonstrated that 6 binds to the BH3 binding site in Bcl-X(L). Our results showed that small-molecule inhibitors of Bcl-2 such as 6 modulate the biological function of Bcl-2, and induce apoptosis in cancer cells with high Bcl-2 expression, while they have little effect on cancer cells with low or undetectable levels of Bcl-2 expression. Therefore, compound 6 can be used as a valuable pharmacological tool to elucidate the function of Bcl-2 and also serves as a novel lead compound for further design and optimization. Our results suggest that the structure-based computer screening strategy employed in the study is effective for identifying novel, structurally diverse, nonpeptide small-molecule inhibitors that target the BH3 binding site of Bcl-2.     

Acylpyrogallols as inhibitors of antiapoptotic Bcl-2 proteins

A series of acylpyrogallols were designed, synthesized, and evaluated as small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound 9 (TM-179) binds to Bcl-2 with an IC50 of 170 nM and to Mcl-1 with a Ki of 37 nM. Compound 9 potently inhibits cell growth and induces apoptosis in human breast and prostate cancer cell lines.     

Small-molecule inhibitors of Bcl-2

Cancer cells with elevated levels of Bcl-2 and the related anti-apoptotic proteins Bcl-x(L), Mcl-1 and Bcl-W are broadly resistant to standard anticancer drugs and other therapeutic modalities. Antisense oligodeoxynucleotides and, more recently, small-molecule ligands for Bcl-2 and Bcl-x(L), sensitize cancer cells to cytotoxic therapies. In some cases, Bcl-2-targeted therapies can function as single therapeutic agents to kill tumor cells, suggesting that Bcl-2 has an important role in the critical functions of cancer cells. The molecular mechanisms of Bcl-2 are not completely understood, therefore, the validation of cytotoxic mechanisms related to Bcl-2 as well as the identification of surrogate markers for Bcl-2 function are significant obstacles for drug development. Despite these problems, two Bcl-2 small-molecule inhibitors are currently undergoing phase I/II clinical trials and several other compounds are in preclinical development. Ongoing studies with these investigational drugs should provide new insights into optimal strategies to disrupt Bcl-2 survival functions to selectively kill cancer cells.     

Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors

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Small-molecule inhibitors of Bcl-2 family proteins as therapeutic agents in cancer

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