靶向癌症干细胞的小分子化合物的研发。
Development of small molecular compounds targeting cancer stem cells.
作者信息
Park Jae-Hyun, Chung Suyoun, Matsuo Yo, Nakamura Yusuke
机构信息
Department of Medicine , The University of Chicago , 900 E 57th street KCBD 6130 , Chicago , IL 60637 , USA . Email:
OncoTherapy Science, Inc. , Kawasaki , 213-0012 , Japan.
出版信息
Medchemcomm. 2016 Nov 11;8(1):73-80. doi: 10.1039/c6md00385k. eCollection 2017 Jan 1.
Abstract
Cancer stem cells (CSCs) are indicated to play critical roles in drug resistance, recurrence, and metastasis of cancer. Although molecular targeted therapies have contributed to the improvement of cancer treatments by targeting vulnerable pathways indispensable to the proliferation and survival of cancer cells, no relevant therapeutic modalities targeting CSCs have been developed yet. This review focuses on MELK (maternal embryonic leucine zipper kinase), TOPK (T-lymphokine-activated killer cell-originated protein kinase), and TTK (tyrosine threonine kinase), which are over-expressed frequently in human cancers and play indispensable roles in the development and maintenance of cancer stem cells. In addition, we will discuss recently developed small molecules for these protein targets, which have shown remarkable anti-tumor efficacies in several preclinical studies.
摘要
癌症干细胞（CSCs）被认为在癌症的耐药性、复发和转移中起关键作用。尽管分子靶向疗法通过靶向癌细胞增殖和存活所必需的脆弱途径，为癌症治疗的改善做出了贡献，但尚未开发出针对癌症干细胞的相关治疗方法。本综述重点关注母源胚胎亮氨酸拉链激酶（MELK）、T淋巴细胞激活的杀伤细胞起源蛋白激酶（TOPK）和酪氨酸苏氨酸激酶（TTK），它们在人类癌症中经常过度表达，并在癌症干细胞的发育和维持中发挥不可或缺的作用。此外，我们将讨论最近针对这些蛋白质靶点开发的小分子，这些小分子在几项临床前研究中显示出显著的抗肿瘤疗效。
相似文献
1
Development of small molecular compounds targeting cancer stem cells.靶向癌症干细胞的小分子化合物的研发。
Medchemcomm. 2016 Nov 11;8(1):73-80. doi: 10.1039/c6md00385k. eCollection 2017 Jan 1.
2
Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells.TOPK和MELK的致癌作用以及小分子抑制剂对肾癌细胞的有效生长抑制作用。
Oncotarget. 2016 Apr 5;7(14):17652-64. doi: 10.18632/oncotarget.7755.
3
Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer.母体胚胎亮氨酸拉链激酶（MELK）抑制剂对小细胞肺癌的有效生长抑制活性。
Oncotarget. 2016 Mar 22;7(12):13621-33. doi: 10.18632/oncotarget.7297.
4
Resistance to Cell Death and Its Modulation in Cancer Stem Cells.癌症干细胞中对细胞死亡的抗性及其调控
Crit Rev Oncog. 2016;21(3-4):203-219. doi: 10.1615/CritRevOncog.2016016976.
5
Functional genomics for breast cancer drug target discovery.乳腺癌药物靶点发现的功能基因组学。
J Hum Genet. 2021 Sep;66(9):927-935. doi: 10.1038/s10038-021-00962-6. Epub 2021 Jul 20.
6
Cell growth inhibition by 3-deoxysappanchalcone is mediated by directly targeting the TOPK signaling pathway in colon cancer.3-脱氧萨普素查尔酮通过直接靶向结肠癌中的 TOPK 信号通路来抑制细胞生长。
Phytomedicine. 2019 Aug;61:152813. doi: 10.1016/j.phymed.2018.12.036. Epub 2018 Dec 31.
7
TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.TOPK通过磷酸化并激活c-Jun来促进肺癌对EGFR酪氨酸激酶抑制剂的耐药性。
Oncotarget. 2016 Feb 9;7(6):6748-64. doi: 10.18632/oncotarget.6826.
8
Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia.母体胚胎亮氨酸拉链激酶（MELK）抑制在急性髓系白血病中的临床前疗效。
Oncotarget. 2014 Dec 15;5(23):12371-82. doi: 10.18632/oncotarget.2642.
9
Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family.母源胚胎亮氨酸拉链激酶（MELK）通过与Bcl-2家族的促凋亡成员Bcl-G相互作用参与乳腺癌发生。
Breast Cancer Res. 2007;9(1):R17. doi: 10.1186/bcr1650.
10
MELK-a conserved kinase: functions, signaling, cancer, and controversy.MELK——一种保守激酶：功能、信号传导、癌症及争议
Clin Transl Med. 2015 Mar 7;4:11. doi: 10.1186/s40169-014-0045-y. eCollection 2015.
引用本文的文献
1
The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration.致癌激酶 TOPK 在银屑病角质形成细胞中上调，并通过调节中性粒细胞浸润促进银屑病进展。
Cell Commun Signal. 2024 Aug 1;22(1):386. doi: 10.1186/s12964-024-01758-9.
2
Design and synthesis of doublecortin-like kinase 1 inhibitors and their bioactivity evaluation.双皮质素样激酶 1 抑制剂的设计与合成及其生物活性评价。
J Enzyme Inhib Med Chem. 2024 Dec;39(1):2287990. doi: 10.1080/14756366.2023.2287990. Epub 2023 Dec 7.
3
CENPA regulates tumor stemness in lung adenocarcinoma.CENPA 调控肺腺癌肿瘤干细胞干性。
Aging (Albany NY). 2022 Jul 11;14(13):5537-5553. doi: 10.18632/aging.204167.
4
PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential.PBK/TOPK：一种具有多种治疗潜力的有效药物靶点。
Cancers (Basel). 2021 May 6;13(9):2232. doi: 10.3390/cancers13092232.
5
Identification of key genes controlling cancer stem cell characteristics in gastric cancer.鉴定控制胃癌中癌症干细胞特征的关键基因。
World J Gastrointest Surg. 2020 Nov 27;12(11):442-459. doi: 10.4240/wjgs.v12.i11.442.
6
The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication.转录因子在胃癌和结直肠癌干细胞识别与根除中的相关性
Front Cell Dev Biol. 2020 Jun 18;8:442. doi: 10.3389/fcell.2020.00442. eCollection 2020.
7
Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones.基于合成生物学构建与生物活性相关的真菌含 decalin 的二萜吡喃酮库。
Nat Commun. 2020 Apr 14;11(1):1830. doi: 10.1038/s41467-020-15664-4.
8
Discovery of selective, antimetastatic and anti-cancer stem cell metallohelices post-assembly modification.选择性、抗转移和抗癌干细胞金属螺旋体的组装后修饰的发现。
Chem Sci. 2019 Jul 18;10(37):8547-8557. doi: 10.1039/c9sc02651g. eCollection 2019 Oct 7.
9
An anticancer Os(II) bathophenanthroline complex as a human breast cancer stem cell-selective, mammosphere potent agent that kills cells by necroptosis.一种抗癌的 Os(II) 二氮菲配合物，作为一种人乳腺癌干细胞选择性的、能够形成乳腺球体的有效试剂，通过坏死性凋亡杀死细胞。
Sci Rep. 2019 Sep 16;9(1):13327. doi: 10.1038/s41598-019-49774-x.
10
Liposomal OTS964, a TOPK inhibitor: a simple method to estimate OTS964 association with liposomes that relies on enhanced OTS964 fluorescence when bound to albumin.脂质体 OTS964，一种 TOPK 抑制剂：一种简单的方法来估计 OTS964 与脂质体的结合，这种方法依赖于 OTS964 与白蛋白结合时增强的荧光。
Drug Deliv Transl Res. 2019 Dec;9(6):1082-1094. doi: 10.1007/s13346-019-00651-0.
本文引用的文献
1
T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer.T-LAK 细胞起源的蛋白激酶（TOPK）作为卵巢癌的预后因素和潜在治疗靶点。
Clin Cancer Res. 2016 Dec 15;22(24):6110-6117. doi: 10.1158/1078-0432.CCR-16-0207. Epub 2016 Jun 22.
2
Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells.TOPK和MELK的致癌作用以及小分子抑制剂对肾癌细胞的有效生长抑制作用。
Oncotarget. 2016 Apr 5;7(14):17652-64. doi: 10.18632/oncotarget.7755.
3
Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor.与MELK抑制剂抗肿瘤活性相关生物标志物的临床前评估
Oncotarget. 2016 Apr 5;7(14):18171-82. doi: 10.18632/oncotarget.7685.
4
Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer.母体胚胎亮氨酸拉链激酶（MELK）抑制剂对小细胞肺癌的有效生长抑制活性。
Oncotarget. 2016 Mar 22;7(12):13621-33. doi: 10.18632/oncotarget.7297.
5
Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer.母源胚胎亮氨酸拉链激酶作为胃癌预后不良的标志物和治疗靶点。
Oncotarget. 2016 Feb 2;7(5):6266-80. doi: 10.18632/oncotarget.6673.
6
Targeting Mitosis in Cancer: Emerging Strategies.靶向癌症有丝分裂：新兴策略。
Mol Cell. 2015 Nov 19;60(4):524-36. doi: 10.1016/j.molcel.2015.11.006.
7
T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.T淋巴细胞激活的杀伤细胞来源的蛋白激酶是FLT3-ITD突变型急性髓系白血病的一个新的治疗靶点。
Oncotarget. 2015 Oct 20;6(32):33410-25. doi: 10.18632/oncotarget.5418.
8
Therapeutic strategies targeting cancer stem cells.针对癌症干细胞的治疗策略。
Cancer Sci. 2016 Jan;107(1):5-11. doi: 10.1111/cas.12817. Epub 2015 Oct 21.
9
Combined expressional analysis, bioinformatics and targeted proteomics identify new potential therapeutic targets in glioblastoma stem cells.联合表达分析、生物信息学和靶向蛋白质组学鉴定胶质母细胞瘤干细胞中的新潜在治疗靶点。
Oncotarget. 2015 Sep 22;6(28):26192-215. doi: 10.18632/oncotarget.4613.
10
Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo.靶向PBK/TOPK可降低胶质瘤起始细胞在体外的生长和存活率，并在体内减弱肿瘤生长。
Mol Cancer. 2015 Jun 17;14:121. doi: 10.1186/s12943-015-0398-x.
Zotero 插件