Actin-Inhibitors

About

Cancer metastasis is the cause of 90% of cancer-related deaths. Current therapies fail to block metastasis effectively. The engine driving metastasis is fueled by actin polymerization. Actin is a globular protein (G-actin) that can polymerize into filamentous F-actin, which forms a three-dimensional network inside all eukaryotic cells. This is critical for cell processes such as cell division, cell locomotion, and chemotactic migration. Therefore, actin is recognized as a strategic target for the development of new anticancer drugs. Actin is targeted by many natural products that display extremely potent cytotoxic activities towards cancer cells. However, these agents alone are unsuitable for clinical use due to their lack of discrimination between the actin of tumorous cells and that of normal tissues. Moreover, their quantities are extremely limited and their chemical synthesis is too demanding to be useful by the pharmaceutical industry. A logical way to overcome these obstacles is to build simplified derivatives of the cytotoxic component of the natural product that can be linked to tumor-seeking antibodies. Current cancer therapies fail to target “actin addiction” of metastatic tumor cells. Targeting actin with inhibitory small molecules could complement existing cytotoxic therapies and protect cancer patients from cancer progression to metastatic disease. Marine toxins, such as Mycalolide B (MycB), are known to be very potent inhibitors of actin polymerization. Queens researchers have created a series of analogs of MycB which could be used as anti-cancer agents alone or as warheads for new ADC constructs. Their effects were tested in a scalable pyrene-actin assay that measures actin polymerization. MycB shows dependent inhibition of pyrene-actin with an IC50 = 0.01 µM. Novel analogs of MycB were synthesize that showed similar activity with IC50s = 0.05 µM. Testing a select compound (BVP-2-13) at low micromolar concentrations (< 5 µM) in ovarian cancer cells (SKOV3) showed disruption of the actin cytoskeleton within minutes of treatment. BVP-2-13 also suppressed the growth of SKOV3 cells at concentrations < 10 µM. Further testing in a motility assay (scratch wound) of BVP-2-13 < 10 µM showed the significant inhibition of cell motility of SKOV3 cells. Finally, BVP-2-13 showed a significant and dose-dependent cytotoxicity of SKOV3 at < 5 µM using the CytoTox-Glo assay. Other analogs are currently being synthesized and as proof-of-concept as an ADC toxin analogs are being conjugated to antibodies for further testing on cancer cells.