Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-09-26
1998-12-01
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540509, 540514, A61K 3155, C07D24314, C07D24324
Patent
active
058439412
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates generally to non-peptidyl inhibitors of farnesyl:protein transferase, an enzyme capable of catalizing farnesylation of p21.sup.ras and related low molecular weight G-proteins. More specifically, the instant inhibitors are analogs of benzodiazepine and structurally related 6-7 fused ring systems. The invention further relates to use of these inhibitors in pharmaceutical compositions where inhibition of posttranslational farnesylation of p21.sup.ras and related proteins is indicated.
BACKGROUND OF THE INVENTION
Proteins encoded by the ras proto-oncogene act as molecular switches responding to growth stimuli and signaling to the intracellular machinery the occurrence of an extracellular event such as binding of a growth hormone to a growth hormone receptor molecule. Binding of the hormone to its receptor (the external signal) switches the ras protein to the "on" position characterized by exchange of ras bound GDP for GTP. The tightly bound GTP in turn stimulates downstream target proteins, ultimately triggering a cascade of reactions leading to specific gene transcription McCormick, Nature 363:15-16 (1993)!. The normal (i.e., non-transformed) ras protein eventually switches to the off position by hydrolyzing bound GTP to GDP and the cell is poised to receive the next external signal.
Mutations to the ras proto-oncogene translate into amino acid substitutions in the GTP binding domain, activating the ras protein (p21.sup.ras) and biasing this molecular switch in the "on" position. Thus, the ras transformed cell behaves like a cell with a faulty switch, signaling extracellular hormone binding when none is present. Cells transformed in this way grow and differentiate in an abnormal way.
Transforming ras genes are the oncogenes most frequently identified in human cancers. Clinical investigations have identified activated ras genes in a wide variety of human neoplasms, including carcinomas, sarcomas, leukemias, and lymphomas. It is estimated that 40% of all human colon cancers and 95% of human pancreatic cancers contain activated ras
Recently, it has been discovered that the ras protein must be properly posttranslationally modified before it can function as a molecular switch. Stable modification of the carboxy terminus of ras proteins appears to be essential for correct localization within the cell membrane so that extracellular signals for cell growth and differentiation can be correctly passed along to the intracellular messengers (see e.g., Gibbs et al., posttranslationally modified by farnesylation of a cysteine residue located four residues from the carboxy terminus, followed by proteolytic cleavage of the three following amino acid residues and methylation of the free cysteine carboxyl. The farnesylation reaction is catalyzed by a 94 Kda heterodimeric Zn.sup.2+ metalloenzyme, farnesyl:protein transferase, which transfers the farnesyl group, a 15 carbon isoprenoid lipid derived from mevalonate (a cholesterol precursor), from farnesyl pyrophosphate to the carboxy terminus cysteine sulfur of rasforming a stable thioether linkage. The farnesyl:protein transferase recognizes the ras carboxy terminus consensus sequence, CAAX, where the cysteine (C) is followed by two aliphatic (A) amino acids (usually valine, leucine, or isoleucine) and 310:583-586 (1984)!. This consensus sequence or motif is frequently referred to as the "CAAX box" and is found in other ras related GTP-binding proteins such as fungal mating factors, nuclear lamins, the gamma subunit of transducin, rhodopsin kinase, and the alpha subunit of cGMP-phosphodiesterase.
Surprisingly, this enzyme does not require intact ras protein for transferase activity and can utilize tetrapeptides with the CAAX motif as suggested that small tetrapeptides like CAAX or nonpeptide analogs thereof could compete with p21.sup.ras for the active site of the transferase and therefore might be of therapeutic utility.
Previously, it had been observed that mutation of the cysteine in the CAAX carboxy sequence of p21.sup.ras to
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Brown Michael S.
Crowley Craig W.
Goldstein Joseph L.
James Guy L.
Marsters, Jr. James C.
Board of Regents University of Texas
Bond Robert T.
Genentech Inc.
Winter Daryl B.
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