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Wrobel, Matthias (2014): Triazolobenzodiazepines and -triazepines as protein interaction inhibitors targeting bromodomains of the BET family. Dissertation, LMU München: Faculty of Chemistry and Pharmacy



Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolobenzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation. Besides SAR studies using high resolution crystal structures, we measured affinity and selectivity of newly synthesized triazolobenzodiazepine and triazolobenzotriazepine derivatives via a protein stability shift assay as well as isothermal titration calorimetry (ITC). Our analysis revealed the importance of the annulated methyltriazole ring for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors!