Rational design of peptide receptor targeted anti-tumor drugs. Ellipticine derivatives of gastrin and cholecystokinin

We have used peptide hormones gastrin and cholecystokinin and their receptors, the cholecystokinin receptors type A and B as model systems to determine the prerequisites for effective receptor targeted drugs. Mechanistic studies of receptor mediated delivery of the hormones into the cells were used for the design and construction of receptor targeted cytotoxic compounds. Our recent data define the requirements for the effective drug, which include a very high intrinsic cytotoxicity of the warhead portion of the construct, sufficient length of the peptide moiety, which is different for different toxic moieties (minimum 6-7 amino acids for ellipticine), and rapid specific hydrolysis in the lysosomes of the linker between the warhead and the peptide or of the peptide. Ellipticine derivatives of cholecystokinin and gastrin illustrate these points. The correctly constructed drugs were found to have IC50 in the subnanomolar range and therapeutic index between 500 and 5000.

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