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

• Applicants: Professor Dr. Markus Heinrich; Professorin Dr. Susanne Mühlich, Ph.D.
• Subject Area: Pharmacology ; Pharmacy ; Cell Biology
• Term: since 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 187824363

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.

• DFG Programme: Research Grants