Aryl-indolyl maleimides as inhibitors of CaMKIIδ. Part 2: SAR of the amine tether

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 7, 2008, Pages 2395-2398

  Levy, Daniel E ^a   Wang, Dan Xiong ^a   Lu, Qing ^a   Chen, Zheng ^a   Perumattam, John ^a   Xu, Yong jin ^a   Higaki, Jeffrey ^a   Dong, Hanmin ^a   Liclican, Albert ^a   Laney, Maureen ^a   Mavunkel, Babu ^a   Dugar, Sundeep ^a  

^a SCIOS INC   (United States)

Author keywords

Calmodulin; Inhibitors; Kinase; Maleimides

Indexed keywords

AMINE; CORE PROTEIN; FUNCTIONAL GROUP; INDOLYLMALEIMIDE DERIVATIVE; MALEIMIDE DERIVATIVE; PROTEIN KINASE (CALCIUM,CALMODULIN); UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CHEMICAL MODEL; DRUG STRUCTURE; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME INHIBITION; NONHUMAN; STRUCTURAL HOMOLOGY; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; AMINES; BENZENE DERIVATIVES; BINDING SITES; CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE TYPE 2; DRUG DESIGN; ENZYME INHIBITORS; INDOLES; MALEIMIDES; MODELS, CHEMICAL; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 41149142050     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.02.058     Document Type: Article

References (14)

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10. An homology model of autoinhibited CaMKIIδ was built based on 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 that best explained the SAR. The accuracy of this model was validated using point mutation studies.
11. Faul M.M., Winneroski L.L., and Krumrich C.A. J. Org. Chem. 63 (1998) 6053
12. 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).
13. The following compounds were obtained from Calbiochem-Novabiochem: 7a (cat # 203294), 7g (cat # 203297), 7l (cat # 203292) and 7m (cat # 557508).
14. The following compounds were obtained from Sigma: 7j (cat # B3681) and 7k (cat # B3556).