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

Molecular Cancer Therapeutics
Mark A CurrierTimothy P Cripe

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 ...Continue Reading

References

Sep 15, 1988·Physical Review A: General Physics·A D Becke
Mar 13, 2003·Molecular Biology of the Cell·Nicole S BryceRon P Weinberger
Jun 8, 2004·Current Cancer Drug Targets·JianYu Rao, Ning Li
Sep 24, 2005·Nature Cell Biology·Manuel ThéryMichel Bornens
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Nov 23, 2005·Bioinformatics·Konstantin ArnoldTorsten Schwede
Aug 24, 2006·Biochimica Et Biophysica Acta·Hideki Yamaguchi, John Condeelis
Oct 5, 2006·Journal of the National Cancer Institute·Nicole M VerrillsMaria Kavallaris
Dec 25, 2007·Acta Crystallographica. Section A, Foundations of Crystallography·Helen M Berman
Jan 21, 2009·Cancer Metastasis Reviews·Alan Hall
Feb 13, 2009·Advances in Experimental Medicine and Biology·David M HelfmanAli Saeed
Oct 1, 2009·Future Medicinal Chemistry·Teresa T BonelloPeter W Gunning
Jun 7, 2011·The EMBO Journal·Yoshinori HiranoToshio Hakoshima
Jun 15, 2011·Nature Cell Biology·Jenny FinkMatthieu Piel
Sep 17, 2011·Developmental Cell·Joshua C SandquistWilliam M Bement
Nov 10, 2011·Bioarchitecture·Galina SchevzovPeter W Gunning
Aug 21, 2012·Bioorganic & Medicinal Chemistry Letters·Liqi HeTai-An Lin
Dec 21, 2012·Pediatric Blood & Cancer·Julie R ParkUNKNOWN COG Neuroblastoma Committee
Jan 22, 2013·Cytoskeleton·Sela T Po'uhaMaria Kavallaris
Sep 11, 2013·Journal of Biomolecular Screening·Howard VindinJustine Stehn
Jan 18, 2014·Molecular Cancer Therapeutics·Eiman MukhtarHasan Mukhtar
Sep 25, 2014·Pediatric Blood & Cancer·Mark A ApplebaumSusan L Cohn
May 15, 2015·Molecular Biology of the Cell·Lauren M Goins, R Dyche Mullins
Aug 5, 2015·Journal of Cell Science·Peter W GunningDaniel P Mulvihill

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Citations

Aug 2, 2018·Biological Chemistry·Susanne Eschenburg, Thomas F Reubold
Mar 17, 2018·Scientific Reports·Anthony J KeeEdna C Hardeman
Jul 25, 2019·Journal of Cell Science·Joyce C M MeiringPeter W Gunning
Dec 2, 2017·The Journal of Biological Chemistry·Salma Pathan-ChhatbarDietmar J Manstein
Oct 30, 2019·Nature Materials·Bo YangMichael P Sheetz
Dec 12, 2018·Journal of Neuro-oncology·Camilla B MitchellGeraldine M O'Neill
Nov 4, 2017·Cancer Research·Christopher C MillsValerie B Sampson
Jan 21, 2021·Cancer Metastasis Reviews·Carmen Ruggiero, Enzo Lalli
Oct 22, 2019·Seminars in Cell & Developmental Biology·Edna C HardemanPeter W Gunning
Mar 25, 2021·Translational Oncology·Rahul Suresh, Roberto J Diaz
Jul 10, 2021·World Journal of Hepatology·Nathan R Jacobs, Pamela A Norton
Dec 30, 2021·Cellular and Molecular Life Sciences : CMLS·Abiola Abdulrahman AyanlajaDianshuai Gao

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