A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors

Abstract

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM (4a) and 5 nM (5) and an apparent Ki value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency.

Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor

“…Afterwards both building blocks (8 and pinacol boronic esters (12, 14, 16 and 17)) were coupled using Suzuki coupling to the arylated hinge-binding motifs (18)(19)(20)(21). The cleavage of the silyl ether protecting group was performed with TBAF to the acyclic derivatives (22)(23)(24)(25) and the ring-closure to the macrocyclic compounds (26)(27)(28)(29) were done by a Mitsunobu reaction under high dilutions. The acyclic derivative (22) was partially deprotected, either by TFA to obtain the acyclic derivative without the BOC group (30), or with LiOH to the acyclic derivative without the methyl ester (31).…”

“…The title compound was synthesized according to the procedure of . 13 (22) was suspended in methylene chloride (2.5 mL) and trifluoroacetic acid (0.75 mg, 6.50 mmol) was added slowly at 0 °C.…”

“…Upregulation of CK2 activity has been linked to tumour progression in multiple cancers such as breast, lung, colon, and prostate, making it an attractive target in cancer therapy [13,17]. Multiple endeavours to target CK2 with small molecules have been explored [18][19][20][21][22][23][24][25].…”

Natural Compounds Isolated from Stachybotrys chartarum Are Potent Inhibitors of Human Protein Kinase CK2

“…It appeared that the compounds fit well in the ATP binding site and create adequate bonds. Stachybotrychromene C is able to create a π-hydrogen bond with the “gatekeeper” residue Ph113 [ 18 ], whereas stachybotrydial acetate and acetoxystachybotrydial acetate bind to Val53 by a π-hydrogen bond ( Figure 2 ).…”