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

DOI: 10.1158/0008-5472.CAN-17-2870 DOI Help

Authors: Mathieu Unbekandt (Cancer Research UK Beatson Institute) , Simone Belshaw (Cancer Research UK Beatson Institute) , Justin Bower (Cancer Research UK Beatson Institute) , Maeve Clarke (Cancer Research UK Beatson Institute) , Jacqueline Cordes (Cancer Research UK Beatson Institute) , Diane Crighton (Cancer Research UK Beatson Institute) , Daniel R. Croft (Cancer Research UK Beatson Institute) , Martin J. Drysdale (Cancer Research UK Beatson Institute) , Mathew J. Garnett (Wellcome Trust Sanger Institute) , Kathryn Gill (Cancer Research UK Beatson Institute) , Christopher Gray (Cancer Research UK Beatson Institute) , David A. Greenhalgh (University of Glasgow) , James A. M. Hall (Wellcome Trust Sanger Institute) , Jennifer Konczal (Cancer Research UK Beatson Institute) , Sergio Lilla (Cancer Research UK Beatson Institute) , Duncan Mcarthur (Cancer Research UK Beatson Institute) , Patricia Mcconnell (Cancer Research UK Beatson Institute) , Laura Mcdonald (Beatson Institute for Cancer Research) , Lynn Mcgarry (The Beatson institute for Cancer Research) , Heather Mckinnon (Cancer Research UK Beatson Institute) , Carol Mcmenemy (University of Glasgow) , Mokdad Mezna (Cancer Research UK Beatson Institute) , Nicholas A. Morrice (Cancer Research UK Beatson Institute) , June Munro (Cancer Research UK Beatson Institute) , Gregory Naylor (Cancer Research UK Beatson Institute) , Nicola Rath (Cancer Research UK Beatson Institute) , Alexander W. Schüttelkopf (Cancer Research UK Beatson Institute) , Mairi Sime (Cancer Research UK Beatson Institute) , Michael F. Olson (Cancer Research UK Beatson Institute; University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cancer Research

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 8659

Abstract: 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.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography