2. Academic Validation
  3. Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

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

  • Mol Cancer Ther. 2017 Aug;16(8):1555-1565. doi: 10.1158/1535-7163.MCT-16-0873.
Mark A Currier 1 2,  Justine R Stehn 3 4,  Ashleigh Swain 3,  Duo Chen 1,  Jeff Hook 3,  Eleanor Eiffe 4,  Andrew Heaton 3 4,  David Brown 3 4,  Brooke A Nartker 1,  David W Eaves 5,  Nina Kloss 3,  Herbert Treutlein 6,  Jun Zeng 7,  Irina B Alieva 3 8,  Vera B Dugina 3 9,  Edna C Hardeman 3,  Peter W Gunning 3,  Timothy P Cripe 10 2
Affiliations

Affiliations

  • 1 Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
  • 2 Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children's Hospital, Columbus, Ohio.
  • 3 School of Medical Sciences, University of New South Wales Australia, Sydney, New South Wales, Australia.
  • 4 Novogen Pty Ltd, Hornsby, New South Wales, Australia.
  • 5 Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
  • 6 Sanoosa Pty. Ltd., Melbourne, Victoria, Australia.
  • 7 MedChemSoft Solutions, Wheelers Hill, Victoria, Australia.
  • 8 Department of Electron Microscopy, A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
  • 9 Mathematical Methods in Biology, A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
  • 10 Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio. Timothy.Cripe@nationwidechildrens.org.
PMID: 28522589 DOI: 10.1158/1535-7163.MCT-16-0873
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.

Figures
Products