Abstract
Abstract Metastatic cancers are the second leading cause of deaths in the USA. RhoA and Cdc42 play critical roles in the regulation of plasticity of cancer cell migration/invasion and cell proliferation. ROCK1/2 and MRCKá/â are downstream kinases in the signaling pathways associated with cancer cell migration and invasion. Hence, we hypothesized that simultaneous targeting of these two kinase families would be an effective therapeutic strategy to block migration, invasion, and growth of metastatic cancers. We have identified DJ4 as a novel inhibitor of ROCK and MRCK kinases. In the cellular functional assays, DJ4 treatment significantly blocked stress fiber formation, and inhibited migration and invasion of multiple cancer cell lines in a concentration dependent manner. To study the critical functional groups required for its activity, we have modified the chemical structure of DJ4 at various functional groups and synthesized several analogs of DJ4 to perform the structural activity relationship (SAR) study for their ROCK1 inhibition. The effectiveness of these compounds were further investigated using National Cancer Institute's drug screening program in 60 human cancer cell lines representing nine different cancer types. These compounds effectively inhibit migration and invasion of multiple cancer cell types. Selected analogs were tested for their anti migration, pro-apoptotic, and anti-proliferative effects in breast cancer cells. Our studies strongly indicate that DJ4 and its analog, DJ110, are potent inhibitors of ROCK1, ROCK2, MERKá and MRCKâ. The results of our finding will be discussed. Citation Format: Dhimant H. Desai, Vijay P. Kale, Jeremy A. Hengst, Taryn E. Dick, Ashley L. Colledge, Shantu G. Amin, Jong K. Yun. In vitro characterization of novel inhibitors of ROCK and MRCK kinases as anticancer agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4805.
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