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Fluorescent biosensors for probing CDK4/cyclin D activity and developing non‐ATP pocket Inhibitors for melanoma, lung cancer and lymphoma (972.2)
Author(s) -
Morris May,
Prevel Camille,
Pellerano Morgan,
Van Thi Nhu Ngoc
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.972.2
Subject(s) - kinase , cancer research , biosensor , anaplastic lymphoma kinase , melanoma , chemistry , lung cancer , biology , biochemistry , medicine , oncology , malignant pleural effusion
CDK4/cyclin D kinase constitutes an attractive pharmacological target in lung cancer, melanoma and lymphoma, associated with mutation or amplification of CDK4, cyclin D or p16INK4a, but efforts to develop tools for detection of this kinase in its native environment, as well as selective inhibitors for therapeutic purposes have remained limited. To this aim we have engineered a fluorescent polypeptide biosensor that reports on CDK4/cyclin D activity in a sensitive and continuous fashion in vitro, in living cells and in biopsies and which allows to monitor response to therapeutics in animal tumour models. We have further designed two biosensors which have been applied to identify competitors of essential protein/protein interfaces between CDK4 and Cyclin D, and allosteric inhibitors that perturb the conformational dynamics of CDK4, respectively, by high throughput screening. These studies highlight the importance of fluorescent biosensors for fundamental research, biomedical developments and drug discovery programmes, providing novel and sensitive approaches to monitor cancer‐associated alterations in protein kinase activities and develop non‐ATP pocket inhibitors. Grant Funding Source : Grants to MCM “Chercheuse d’Avenir” Région Languedoc‐Roussillon, ARC and INCA