Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

“…Second, it possesses remarkable affinity toward CK2, and its cellular activity hasb een demonstrated. First, the oligo-aspartate moiety present in previously reported compounds [18,19] was replaced with the corresponding carboxylate-rich peptoid chain comprising N-carboxymethylglycine (iminodiacetic acid, Ida) residues. ATBi se xpected to give two essential polar interactions with the ATPp ocket of CK2.…”

“…The carboxylate moiety gives an ion-ioni nteraction with the ammonium ion of Lys68, andn itrogen of the thiazole ring gives ac anonical hydrogen bond to the hinge region of CK2. [24] On the other hand, the exocyclic amino group connected to the thiazole ring of the ATBf ragment was expected to point outward from the ATPp ocket of CK2 and thus appeared as as uitable functional group for connecting the linker and peptoid moiety.N evertheless, relative to the biligandi nhibitors previously designed by us, [17][18][19] the expected position of the 2amino group of thiazole is located farther away from the binding site of the substrate protein. This positioning of interacting units presumedt he application of al onger linker between the ATP-competitive fragment and the peptoid.…”

“…ARC-S-S-transport vector conjugates (18,19,20) Heterodimerization of transport vectors 15-17 with Spyr-or Npysactivated sulfhydryl group and ARC-772-SH (11)w as carried out according to published procedure (Scheme S2). [61] The solution of 11 in aqueous ACN/0.1 %A cOH (1:1 by volume) was added dropwise over 5min to am olar equivalent of 15, 16,o r17 in NH 4 OAc (1 m in H 2 Oo ri nH 2 O/ACN 1:1m ixture to increase solubility).…”

“…[17][18][19][20] Both good cellular accumulation and appropriate intracellular compartmentalization are criticalf actorsf or as uccessful PK-inhibitor-based drug. CX-4945, the only ATP-competitive CK2 inhibitor that has reached clinicalt rials, is the mosts uccessful example.…”

“…Combining the substrate protein-and nucleotidecompetitive inhibitors into ab iligand inhibitor could increase the inhibitory potency as well as cell plasma membrane penetration properties of the compound. [17][18][19][20] Both good cellular accumulation and appropriate intracellular compartmentalization are criticalf actorsf or as uccessful PK-inhibitor-based drug. As an example, the intracellular concentration of imatinib (Glee-vec) is substantially higher than in the incubation solution or blood plasma,w hich could explain the effectiveness of the drug in causing apoptosis of leukemic cells.…”