Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer

Unbekandt, M. et al. (2018) Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer. Cancer Research, 78(8), pp. 2096-2114. (doi: 10.1158/0008-5472.CAN-17-2870) (PMID:29382705) (PMCID:PMC5901721)

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The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Munro, Dr June and Greenhalgh, Dr David and Croft, Dr Daniel and Belshaw, Miss Simone and Gill, Kathryn and McConnell, Mrs Patricia and Lilla, Dr Sergio and Drysdale, Dr Martin and Bower, Professor Justin and Sime, Dr Mairi and MCMENEMY, Carol and Rath, Dr Nicola and Mezna, Dr Mokdad and Crighton, Dr Diane and Naylor, Gregory and Gray, Dr Christopher and McGarry, Ms Lynn and Unbekandt, Dr Mathieu and McDonald, Dr Laura and Olson, Professor Michael and Morrice, Dr Nicholas
Authors: Unbekandt, M., Belshaw, S., Bower, J., Clarke, M., Cordes, J., Crighton, D., Croft, D. R., Drysdale, M. J., Garnett, M. J., Gill, K., Gray, C., Greenhalgh, D. A., Hall, J. A.M., Konczal, J., Lilla, S., McArthur, D., McConnell, P., McDonald, L., McGarry, L., McKinnon, H., McMenemy, C., Mezna, M., Morrice, N. A., Munro, J., Naylor, G., Rath, N., Schüttelkopf, A. W., Sime, M., and Olson, M. F.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN (Online):1538-7445
Published Online:30 January 2018
Copyright Holders:Copyright © 2018 American Association for Cancer
First Published:First published in Cancer Research 78(8): 2096-2114
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
576111Development of a novel drug targeting MRCK and ROCKII for the treatment of invasive and/or metastatic cancerMichael OlsonMedical Research Council (MRC)MR/J005126/1ICS - BEATSON INSTITUTE FOR CANCER RES.