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

巨核细胞白血病1型和2型（MKL 1和2）是血清反应因子（SRF）的转录辅激活因子，其协调基本的生物学过程，如细胞增殖、迁移、粘附和分化。近年来，SRF和MKL 1/2在肝细胞癌（HCC）形成和发展中的作用受到了广泛关注。尽管HCC已成为全球癌症相关死亡的第二大常见原因，但HCC形成的分子机制在很大程度上仍不清楚，治疗选择非常有限。Muehlich实验室的工作表明，肝癌1（DLC 1）中的β-淀粉样蛋白的丢失导致MKL 1和2的核定位和激活，导致细胞增殖和迁移增加。 DLC 1是一种肿瘤抑制基因，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MKL 1和MKL-2及其靶基因Myoferlin在体外和体内引起由癌基因诱导的衰老（OIS）引起的HCC细胞的生长停滞。OIS作为一种肿瘤抑制机制，因此在癌症治疗中获得了药物干预的考虑。在施用TRPM 7抑制剂NS 8593后诱导OIS代表了HCC治疗的新治疗方法。TRPM 7阻断通过OIS抑制MKL/SRF靶基因表达和HCC异种移植物生长。NS 8593调节TRPM 7和Ca 2+激活的钾通道（SK通道）。该提案的目的是通过针对MKL 1抑制和衰老诱导选择性的靶向结构变化来优化NS 8593，并获得有关TRPM 7通道抑制剂结合位点的数据。此外，我们将在药物再利用方面使用其他化合物，并评估可能的联合疗法来抑制新鉴定的TRPM 7-MKL 1轴。CAM-和HCC模型的最有前途的候选人将允许判断的疗效的新型抑制剂的治疗DLC 1缺陷的HCC。

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.