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Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy With Microtubule Drugs

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy With Microtubule Drugs

Mark A Currier, Justine R Stehn, Ashleigh Swain, Duo Chen, Jeff Hook, Eleanor Eiffe, Andrew Heaton, David Brown, Brooke A Nartker, David W Eaves, Nina Kloss, Herbert Treutlein, Jun Zeng, Irina B Alieva, etc.

Mol Cancer Ther. 2017 Aug;16(8):1555-1565.

PMID: 28522589

Abstract:

Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are well-established, antiactin 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 antitropomyosin analogues for anticancer 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 antimicrotubule 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 antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin 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 antimicrotubule agents and are tolerated together in vivo This combination warrants further study. Mol Cancer Ther; 16(8); 1555-65. ©2017 AACR.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1128165865	TR100		1128165-86-5	Price

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