11UC
Crystal structure of Casein Kinase 2 (CK2) alpha in complex with BMS-595
This is a non-PDB format compatible entry.
Summary for 11UC
| Entry DOI | 10.2210/pdb11uc/pdb |
| Descriptor | Casein kinase II subunit alpha, methyl [4-chloro-3-{[(4S)-3-cyano-8-(cyclopropylamino)imidazo[1,2-b]pyridazin-6-yl]amino}-5-(4-methylpiperazin-1-yl)phenyl]carbamate, MANGANESE (II) ION, ... (5 entities in total) |
| Functional Keywords | kinase, csnk2a1, ckii, ck2a1, ckii alpha, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40653.10 |
| Authors | |
| Primary citation | Tarby, C.M.,Hart, A.,Wan, H.,He, L.,Tokarski, J.,Fink, B.,Zhao, Y.,Huynh, T.,Gavai, A.,Zimmermann, K.,Vite, G.,Vyas, D.,Inghrim, J.,Obermeier, M.,Fura, A.,Elzinga, P.,Hunt, J.,Roongta, U.,Henley, B.,Lippy, J.,Mathur, A.,Wu, D.R.,Li, P.,Raghavan, N.,Everlof, G.,Rupnow, B.,Lee, F.,Fargnoli, J.,Tredup, J.,Kiefer, S.E.,Calambur, D.,Gupta, A.,Vetrichelvan, M.,Subbaiah, M.A.M.,Purandare, A.V. Discovery of BMS-159, an Orally Active Imidazotriazine Pan-CK2 Inhibitor for the Treatment of Cancer. Acs Med.Chem.Lett., 17:1145-1153, 2026 Cited by PubMed Abstract: Casein kinase 2 (CK2), comprising the catalytic subunits CK2α and CK2α', is a highly conserved and constitutively active serine/threonine kinase that is implicated in oncogenic signaling and tumor maintenance, making it an attractive therapeutic target. We report a medicinal chemistry campaign that delivered an imidazotriazine pan-CK2 series culminating in BMS-135 and its phosphate prodrug BMS-159. Structure-guided design enabled a scaffold hop from imidazopyridazine to imidazotriazine that improved kinome selectivity while preserving critical hinge and Lys68 interactions. Iterative SAR optimization mitigated hERG liability by modulating distal basicity and enhanced metabolic stability via a C8 -ethyl substitution that blocked N-dealkylation, delivering BMS-135 as a sub-nanomolar CK2 inhibitor with favorable ADMET properties and robust antitumor efficacy across xenograft and patient-derived xenograft models. Subsequent pharmaceutical optimization through a prodrug strategy afforded BMS-159, which markedly improved solubility and enabled oral delivery of the parent with acceptable bioavailability and pharmacokinetic properties suitable for further development. PubMed: 42157838DOI: 10.1021/acsmedchemlett.6c00089 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.962 Å) |
Structure validation
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