Novel inhibitors of the transcriptional coactivators MKL1 and -2 for tumor therapy

用于肿瘤治疗的转录共激活因子 MKL1 和 -2 的新型抑制剂

• 批准号: 187824363
• 负责人: Professor Dr. Markus Heinrich
• 金额: --
• 依托单位: Department Chemie und Pharmazie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/187824363?language=en
• 关键词: Novel; inhibitors; transcriptional; coactivators; MKL1

Megakaryoblastic Leukemia 1 and 2 (MKL1 and 2) are transcriptional coactivators of Serum Response Factor (SRF) that orchestrate fundamental biological processes such as cell proliferation, migration, adhesion and differentiation. In recent years, the role of SRF and MKL1/2 in hepatocellular carcinoma (HCC) formation and progression has received considerable attention. Despite HCC has emerged as the second most common cause of cancer-related mortality worldwide, the molecular mechanisms of HCC formation remain largely unknown and the therapeutic options are very limited. Work from the Muehlich laboratory revealed that loss of Deleted in liver cancer 1 (DLC1) leads to nuclear localization and activation of MKL1 and 2, resulting in increased cell proliferation and migration. DLC1 is a tumor suppressor whose allele is lost in 50% of liver, mamma and lung carcinomas and 70% of colon carcinomas. Moreover, targeting MKL1 and -2 and its target gene Myoferlin provokes a growth arrest in HCC cells in vitro and in vivo provoked by oncogene-induced senescence (OIS). OIS acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. The induction of OIS upon administration of the TRPM7 inhibitor NS8593 represents a novel therapeutic approach for HCC therapy. TRPM7 blockade inhibits MKL/SRF target gene expression and HCC xenograft growth by OIS. NS8593 modulates the TRPM7 and Ca2+-activated potassium channels (SK channels). The aim of this proposal is to optimize NS8593 by targeted structural variations regarding the selectivity of MKL1 inhibition and senescence induction, and obtain data about the binding site of the inhibitors at the TRPM7 channel. Furthermore, we will employ other compounds in terms of drug repurposing and evaluate a possible combination therapy for inhibition of the newly identified TRPM7-MKL1 axis. CAM- and HCC models of the most promising candidates will allow the judge the efficacy of the novel inhibitors for the therapy of DLC1-deficient HCCs.

巨核细胞白血病 1 和 2（MKL1 和 2）是血清反应因子 (SRF) 的转录共激活因子，可协调细胞增殖、迁移、粘附和分化等基本生物过程。近年来，SRF和MKL1/2在肝细胞癌（HCC）形成和进展中的作用受到广泛关注。尽管 HCC 已成为全球癌症相关死亡的第二大常见原因，但 HCC 形成的分子机制仍然很大程度上未知，治疗选择也非常有限。 Muehlich 实验室的工作表明，肝癌缺失 1 (DLC1) 的缺失会导致 MKL1 和 2 的核定位和激活，从而导致细胞增殖和迁移增加。 DLC1 是一种肿瘤抑制因子，其等位基因在 50% 的肝癌、乳腺癌和肺癌以及 70% 的结肠癌中丢失。此外，靶向 MKL1 和 -2 及其靶基因 Myoferlin 会在体外和体内引起由癌基因诱导衰老 (OIS) 引起的 HCC 细胞生长停滞。 OIS 作为一种肿瘤抑制机制，因此在癌症治疗中的药物干预得到了考虑。 TRPM7 抑制剂 NS8593 诱导 OIS 代表了一种新的 HCC 治疗方法。 TRPM7 阻断通过 OIS 抑制 MKL/SRF 靶基因表达和 HCC 异种移植物生长。 NS8593 调节 TRPM7 和 Ca2+ 激活的钾通道（SK 通道）。该提案的目的是通过关于 MKL1 抑制和衰老诱导的选择性的靶向结构变化来优化 NS8593，并获得有关抑制剂在 TRPM7 通道上的结合位点的数据。此外，我们将在药物再利用方面使用其他化合物，并评估抑制新确定的 TRPM7-MKL1 轴的可能联合疗法。最有希望的候选者的 CAM 和 HCC 模型将有助于判断新型抑制剂治疗 DLC1 缺陷型 HCC 的疗效。