Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival. TBID, displays toward HIPK2 unprecedented efficacy with IC50 of 0.33 μM and selectivity (Gini coefficient 0.592 out of a panel of 76 kinases). The other two members of the HIPK family, HIPK1 and HIPK3, are also inhibited by TBID, although not as efficient as HIPK2. The mode of action of TBID is competitive with respect to ATP, consistent with modelling. TBID interacts with the hinge region through hydrophobic interactions between Val 213, Val 261, Phe 277, Leu 280, Met 331, Ile 345, and the tetrabromine moiety, while the symmetric nitrogen atom at position 3 interacts with the catalytic Lys 228, thus playing a crucial role in the binding architecture.