Thiazole- and selenazole-comprising high-affinity inhibitors possess bright microsecond-scale photoluminescence in complex with protein kinase CK2

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 18; pp. 5062 - 5068
• Main Authors: Vahter, Jürgen, Viht, Kaido, Uri, Asko, Manoharan, Ganesh babu, Enkvist, Erki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2018; Elsevier
• Subjects: Biochemistry & Molecular Biology; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Fluorescence; Fluorescence Polarization; Fluorescent Dyes - chemistry; Humans; Life Sciences & Biomedicine; Molecular Structure; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Pharmacology & Pharmacy; Photochemical Processes; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology; Time Factors; CANCER-CELLS; APOPTOSIS; HEAD; DESIGN; ANGIOGENESIS; ASSOCIATION; LIFETIME; PROBES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.09.003

[Display omitted] A previously disclosed protein kinase (PK) CK2-selective inhibitor 4-(2-amino-1,3-thiazol-5-yl)benzoic acid (ATB) and its selenium-containing counterpart (ASB) revealed remarkable room temperature phosphorescence when bound to the ATP pocket of the protein kinase CK2. Conjugation of these fragments with a mimic of CK2 substrate peptide resulted in bisubstrate inhibitors with increased affinity towards the kinase. Attachment of the fluorescent acceptor dye 5-TAMRA to the conjugates led to significant enhancement of intensity of long-lifetime (microsecond-scale) photoluminescence of both sulfur- and selenium-containing compounds. The developed photoluminescent probes make possible selective determination of the concentration of CK2 in cell lysates and characterization of CK2 inhibitors by means of time-gated measurement of photoluminescence.