Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents.
A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
deSolms, SJ; Ciccarone, TM; MacTough, SC; Shaw, AW; Buser, CA; Ellis-Hutchings, M; Fernandes, C; Hamilton, KA; Huber, HE; Kohl, NE; Lobell, RB; Robinson, RG; Tsou, NN; Walsh, ES; Graham, SL; Beese, LS; Taylor, JS
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