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 o f a signal transduction pathway activated by phospholipase C. Drugs th at block the ability of calmodulin to bind to and activate its target enzymes inhibit the growth of a wide variety of malignant cells. To id entify more potent and selective inhibitors of this potential target f or new drug development, we studied two recently synthesized compounds , KS-501 and KS-502, for their activity against calmodulin-sensitive e nzymes and for their ability to block the growth of parental and multi drug-resistant leukemic cells. KS-501 and KS-502 inhibited the activat ion of a calmodulin-sensitive cyclic nucleotide phosphodiesterase. The mechanism of enzyme inhibition was through interfering with calmoduli n 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 c ompound inhibited the activation of calmodulin kinase I and II, but ha d less effect against cyclic adenosine 3',5'-monophosphate (cyclic AMP )-sensitive kinase. KS-501 was also more effective than KS-502 in inhi biting the growth of sensitive L1210 leukemic lymphocytes. Both compou nds were less effective inhibitors of multidrug-resistant L1210 leukem ia than of the parental line. These studies identify a new class of ca lmodulin 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.