Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While anti-microtubule drugs are well-established, anti-actin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other anti-tropomyosin analogues for anti-cancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1 containing filaments, its cytotoxicity potency and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with anti-microtubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane anti-microtubule agents. In vivo, combination treated animals bearing human neuroblastoma xenografts treated with etiher anti-tropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared to control and either drug alone. Anti-tropomyosin combined with vincristine resulted in G2/M phase arrest, disruption of mitotic spindle formation and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to anti-microtubule agents and are tolerated together in vivo. This combination warrants further study.
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