Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer.

IF 2.3 4区医学 Q3 ONCOLOGY

Current cancer drug targets Pub Date : 2024-01-01 DOI:10.2174/0115680096272757231211113206

Gerhard Hamilton, Sandra Stickler, Barbara Rath

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引用次数: 0

Abstract

Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.

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溴域蛋白导向药物与小细胞肺癌中的 MYC。

小细胞肺癌（SCLC）的预后很差。除了肿瘤抑制因子 TP53 和 RB1 失活外，这种神经内分泌癌还经常过度表达肿瘤促进因子 MYC 和旁系亲属。SCLC对二线化疗表现出高度耐药性，迄今为止，所有新型药物和靶向治疗的尝试都未能获得较好的生存率。MYC 及其对映体在致癌过程中起着关键作用，可协调增殖、凋亡、分化和新陈代谢。在SCLC中，MYC-L和MYC调控SCLC细胞从A型（ASCL1表达）向其他SCLC亚型的神经内分泌去分化。由于缺乏合适的结合口袋，以 MYC 为靶点抑制肿瘤生长十分困难，最先进的小蛋白抑制剂 Omomyc 的疗效也很有限。特异性BET抑制剂可减少这种致癌驱动因子的表达，从而通过激活MYC转录的溴域（BET）蛋白BRD4间接靶向MYC。本文讨论了新型 BET 定向蛋白水解靶向嵌合体（PROTACs），它们在 SCLC 中显示出很高的抗增殖活性。特别是ARV825，它专门靶向BRD4，对SCLC细胞系表现出卓越的细胞毒性作用，可能成为SCLC联合化疗的重要辅助药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current cancer drug targets 医学-肿瘤学

CiteScore

5.40

自引率

0.00%

发文量

105

审稿时长

1 months

期刊介绍： Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.