Kufareva, Irina; Bestgen, Benoit; Brear, Paul; Prudent, Renaud; Laudet, Beatrice; Moucadel, Virginie; Ettaoussi, Mohamed; Sautel, Celine F.; Krimm, Isabelle; Engel, Matthias; Filhol, Odile; Borgne, Marc Le; Lomberget, Thierry; Cochet, Claude; Abagyan, Ruben published the artcile< Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors>, Reference of 23077-43-2, the main research area is CK2 inhibitor cell growth apoptosis breast cancer.
CK2 is a constitutively active protein kinase overexpressed in numerous malignancies. Interaction between CK2a and CK2β subunits is essential for substrate selectivity. The CK2a/CK2β interface has been previously targeted by peptides to achieve functional effects; however, no small mols. modulators were identified due to pocket flexibility and open shape. Here we generated numerous plausible conformations of the interface using the fumigation modeling protocol, and virtually screened a compound library to discover compound 1 that suppressed CK2a/CK2β interaction in vitro and inhibited CK2 in a substrate-selective manner. Orthogonal SPR, crystallog., and NMR experiments demonstrated that 4 and 6, improved analogs of 1, bind to CK2a as predicted. Both inhibitors alter CK2 activity in cells through inhibition of CK2 holoenzyme formation. Treatment with 6 suppressed MDA-MB231 triple neg. breast cancer cell growth and induced apoptosis. Altogether, our findings exemplify an innovative computational-exptl. approach and identify novel non-peptidic inhibitors of CK2 subunit interface disclosing substrate-selective functional effects.
Scientific Reports published new progress about Apoptosis. 23077-43-2 belongs to class indole-building-block, and the molecular formula is C9H6FNO2, Reference of 23077-43-2.
Referemce:
Indole alkaloid derivatives as building blocks of natural products from Bacillus thuringiensis and Bacillus velezensis and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles