Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold.

CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3- d ]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC 50 values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC 50 value of 36.7 nM and a notable cellular activity with a GI 50 of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range. [Display omitted] • We have discovered a new basic scaffold with inhibitory activity against CK2. • Optimization afforded compound 10b with an IC 50 of 36.7 nM against purified CK2α. • None of the frequently reported off-target kinases was inhibited by 10b. • 10b inhibited CK2-mediated substrate phosphorylations in cells. • 10b was more potent to induce cell death than CX-4945 and SGC-CK2-1. [ABSTRACT FROM AUTHOR]