Effects of KS-501, KS-502 and their enantiomers on calmodulin-sensitive enzyme activity and cellular proliferation.
Calmodulin plays an important role in cellular proliferation as part of a signal transduction pathway activated by phospholipase C. Drugs that block the ability of calmodulin to bind to and activate its target enzymes inhibit the growth of a wide variety of malignant cells. To identify more potent and selective inhibitors of this potential target for new drug development, we studied two recently synthesized compounds, KS-501 and KS-502, for their activity against calmodulin-sensitive enzymes and for their ability to block the growth of parental and multidrug-resistant leukemic cells. KS-501 and KS-502 inhibited the activation of a calmodulin-sensitive cyclic nucleotide phosphodiesterase. The mechanism of enzyme inhibition was through interfering with calmodulin activation rather than through a direct effect on the enzyme. KS-501 was more potent than KS-502 and was studied in greater detail. This compound inhibited the activation of calmodulin kinase I and II, but had less effect against cyclic adenosine 3',5'-monophosphate (cyclic AMP)-sensitive kinase. KS-501 was also more effective than KS-502 in inhibiting the growth of sensitive L1210 leukemic lymphocytes. Both compounds were less effective inhibitors of multidrug-resistant L1210 leukemia than of the parental line. These studies identify a new class of calmodulin inhibitor, with selectivity for calmodulin-dependent kinases over cyclic AMP-dependent protein kinase. Since the total synthesis of the KS-compounds has been accomplished, it should now be possible to develop derivatives with greater activity and selectivity.
Hait
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WN
Yale University School of Medicine, Department of Medicine, New Haven, CT 06510, USA.
Gesmonde
J
J
Cheng
E
E
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D062385:Hydroxybenzoates / Q000737:chemistry / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D002147:Calmodulin; D062385:Hydroxybenzoates; C060469:KS 502; C060468:KS 501; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1