Effective therapeutic options are limited for the treatment of liver, lung, renal, ovarian, endometrial and pancreatic cancer. Successive second- and third-line therapies do not add meaningful responses besides adding numerous life-debilitating toxicities. In order to improve the survival rate of patients diagnosed with these lethal malignancies, identification of molecular targets driving the carcinogenesis and development of targeted therapies against oncogenes is needed. Septins are proteins that form filamentous structures, which function primarily in the spatial organization and compartmentalization of many cellular processes, such as cell division and migration, chromosomal dynamics and protein secretion. Altered expression and gene mutation of septins have been identified in multiple malignancies, which makes them an attractive candidate for development of targeted cancer therapies.
We have generated small molecule septin inhibitors (UR214-1 to -11). UR214-7 and UR214-9 cause S-phase cell cycle arrest, inhibit important oncogene HER2 selectively and disable septin-2 dynamics in cancer cells. Additionally, treatment with UR214 analogs block secretion of HE4, a marker that has been linked with malignant types of cancer.
Among these compounds, several UR214 analogs appeared to be much more efficacious at suppressing cell viability and proliferation in ovarian and endometrial cancer cells compared to the only existing septin inhibitor forchlorfenuron (FCF). Our finding that UR214 analogs disrupt HE4 secretion provides a novel approach to mitigate HE4 instituted attributes of malignancies.
Cancer (liver, lung, renal, ovarian, endometrial and pancreatic cancer).
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