Pyrimidine-based inhibitors of CaMKIIδ

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 7, 2008, Pages 2404-2408

  Mavunkel, Babu ^a   Xu, Yong jin ^a   Goyal, Bindu ^a   Lim, Don ^a   Lu, Qing ^a   Chen, Zheng ^a   Wang, Dan Xiong ^a   Higaki, Jeffrey ^a   Chakraborty, Indrani ^a   Liclican, Albert ^a   Sideris, Steve ^a   Laney, Maureen ^a   Delling, Ulrike ^a   Catalano, Rosanne ^a   Higgins, Linda S ^a   Wang, Hui ^a   Wang, Jing ^a   Feng, Ying ^a   Dugar, Sundeep ^a   Levy, Daniel E ^a  

^a SCIOS INC   (United States)

Author keywords

Calmodulin; Inhibitors; Kinase; Pyrimidines

Indexed keywords

ADENOSINE TRIPHOSPHATE; PROTEIN KINASE (CALCIUM,CALMODULIN); PROTEIN KINASE (CALCIUM,CALMODULIN) INHIBITOR; PROTEIN KINASE INHIBITOR; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG IDENTIFICATION; DRUG STRUCTURE; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; BINDING, COMPETITIVE; CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE TYPE 2; DRUG DESIGN; ENZYME INHIBITORS; MODELS, CHEMICAL; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 41149154595     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.02.056     Document Type: Article

References (10)

1. Levy D.E., Wang D.-X., Lu Q., Chen Z., Perumattam J., Xu Y.-J., Liclican A., Higaki J., Dong H., Laney M., Mavunkel B., and Dugar S. Bioorg. Med. Chem. Lett. 18 (2008) 2390
2. Levy D.E., Wang D.-X., Lu Q., Chen Z., Perumattam J., Xu Y.-J., Higaki J., Dong H., Liclican A., Laney M., Mavunkel B., and Dugar S. Bioorg. Med. Chem. Lett. 18 (2008) 2395
3. Lu Q., Chen Z., Perumattam J., Wang D.-X., Liang W., Xu Y.-J., Do S., Bonaga L., Higaki J., Dong H., Liclican A., Sideris S., Laney M., Dugar S., Mavunkel B., and Levy D.E. Bioorg. Med. Chem. Lett. 18 (2008) 2399
4. Zapf A. In: Beller M., and Bolm C. (Eds). Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals. 2nd ed. (2004), Wiley-VCH, Weinheim 1344
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6. 2, 8.3 μg/ml calmodulin, 25 μM [His 5] Autocamtide-2, 120 nM [g-33P]ATP) and incubated at RT for 3 min. Reactions were terminated by transferring 25 μl to a UNIFILTER 96-well P81microplate (Whatman, UK), pre-wet with 15 μl 1% phosphoric acid. After 10 min, the plate was washed three times with 1% phosphoric acid and one time with 95% ethanol on a BiomekFX (Beckman-Coulter, CA) equipped with a vacuum manifold. Plates were dried for approximately 60 min, scintillant was added to the wells, and the plates were read on a TopCount NXT Microplate Scintillation and Luminescence Counter (Perkin-Elmer, MA).
7. An homology model of autoinhibited CaMKIIδ was built based on the crystal structure 1A06 of autoinhibited rat CaMKI. Because rat CaMKI shows high sequence homology with CaMKIIδ, this model was used to study inhibitors that were not ATP competitive. Due to the lack of availability of a crystal structure of activated CaMKIIδ, homology models were built based on crystal structures 1CDK, 1PHK, and 1KOB. From these homology models, we selected the one best explained the SAR. The accuracy of this model was validated using point mutation studies.
8. Amantini D., Beleggia R., Fringuelli F., Pizzo F., and Vaccaro L. J. Org. Chem. 69 (2004) 2896
9. 50 values were determined by an ELISA assay of cell lysate measuring intracellular vimentin phosphorylated at Ser82 (Delling, Catalano, Wang, Higgins, unpublished).
10. Solvation energy calculations were generated using ZAP (Openeye Scientific Software).