Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer
| Autor: | Diane Crighton, Duncan McArthur, Nicholas A. Morrice, Daniel R. Croft, Michael F. Olson, Simone Belshaw, Mokdad Mezna, Carol McMenemy, Gregory Naylor, Jennifer Konczal, James Hall, Alexander W. Schüttelkopf, Jacqueline Cordes, Heather McKinnon, Maeve Clarke, June Munro, Mathieu Unbekandt, Patricia McConnell, David A. Greenhalgh, Sergio Lilla, Nicola Rath, Kathryn Gill, Mairi Sime, Mathew J. Garnett, Justin Bower, Martin J. Drysdale, Laura McDonald, Lynn McGarry, Christopher A. Gray |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Skin Neoplasms Cytoskeleton organization Pyridines Mice Nude Antineoplastic Agents medicine.disease_cause Myotonin-Protein Kinase Article Mice 03 medical and health sciences Cell Line Tumor Drug Discovery medicine Animals Humans Pyrroles ROCK1 Phosphorylation Protein Kinase Inhibitors Drug discovery Chemistry Kinase Autophosphorylation Cancer medicine.disease Xenograft Model Antitumor Assays Disease Models Animal HEK293 Cells Pyrimidines 030104 developmental biology Oncology Cancer cell Carcinoma Squamous Cell Cancer research Carcinogenesis |
| Zdroj: | Cancer Research. 78:2096-2114 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-2870 |
| Popis: | 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 morphologic 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 antiproliferative effects with greatest activity in hematologic 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. Significance: The development of selective small-molecule inhibitors of the Cdc42-binding MRCK kinases reveals their essential roles in cancer cell viability, migration, and invasive character. Cancer Res; 78(8); 2096–114. ©2018 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|