MINING THE NATIONAL-CANCER-INSTITUTE ANTICANCER DRUG DISCOVERY DATABASE - CLUSTER-ANALYSIS OF ELLIPTICINE ANALOGS WITH P53-INVERSE AND CENTRAL NERVOUS SYSTEM-SELECTIVE PATTERNS OF ACTIVITY

The United States National Cancer Institute conducts an anticancer dru g discovery program in which similar to 10,000 compounds are screened every year in vitro against a panel of 60 human cancer cell lines from different organs. To date, similar to 62,000 compounds have been test ed in the program, and a large amount of information on their activity patterns has been accumulated. For the current study, anticancer acti vity patterns of 112 ellipticine analogs were analyzed with the use of a hierarchical clustering algorithm. A dramatic coherence between mol ecular structures and their activity patterns could be seen from the c luster tree: the first subgroup (compounds 1-66) consisted principally of normal ellipticines, whereas the second subgroup (compounds 67-112 ) consisted principally of N-2-alkyl-substituted ellipticiniums. Almos t all apparent discrepancies in this clustering were explainable on th e basis of chemical transformation to active forms under cell culture conditions. Correlations of activity with p53 status and selective act ivity against cells of central nervous system origin made this data se t of special interest to us. The ellipticiniums, but not the elliptici nes, were more potent on average against p53 mutant cells than against p53 wild-type ones (i.e., they seemed to be ''p53-inverse'') in this short term assay. This study strongly supports the hypothesis that ''f ingerprint'' patterns of activity in the National Cancer Institute in vitro cell screening program encode incisive information on the mechan isms of action and other biological behaviors of tested compounds. Ins ights gained by mining the activity patterns could contribute to our u nderstanding of anticancer drugs and the molecular pharmacology of can cer.