Isoprenyl transferase inhibitors

Details Isoprenyl transferase inhibitors Isoprenyl transferase inhibitors

1997-03-19

1998-11-24

Lambkin, Deborah C.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549321, 549496, 560 9, 562426, 546329, 544162, 564204, 564197, 564198, 564162, 564163, 564193, 564199, C07D33322, C07D30702, C07C32100, C07C23300

Patent

active

058409181

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention concerns peptidomimetics useful in the treatment of human cancers.
Ras is an oncogene prevalent in over 20% of all human cancers. In particular, ras oncogenes are found in approximately 30% of all lung cancer, 30% of all myeloid leukemia, 50% of all colorectal carcinoma, and 90% of all pancreatic carcinoma. Barbacid, M., Ann. Rev. Biochem., 56:779 (1987), Bos, J. L., Cancer Res. 49:4682 (1989). Examples of ras mutations include H-ras, K-ras, and N-ras.
Like other members of the superfamily of small GTP-hydrolyzing proteins, ras-encoded proteins require post-translational processing for membrane association and biological function. Maltese, W. A., FASEB Journal, 4:3319 (1990), Hancock, J. F. et al., Cell, 57:1167 (1989).
The post-translational processing of the ras protein is signalled by a short carboxy terminus consensus sequence, a CAAX box, indicating which isoprenyl group (farnesyl or geranylgeranyl) is to be attached. For farnesylated proteins, such as Ras, lamin B, and .gamma.-transducin, C is cysteine, A is an aliphatic amino acid, and X is methionine, serine, or glutamine. Geranylgeranylated proteins such as Rap, Rab, Rho and other small GTP-binding proteins, have similar CAAX sequences in which X is usually leucine, or occasionally phenylalanine.
Post-translational processing of the ras-encoded protein includes at least three steps. First, reaction with farnesyl pyrophosphate attaches a farnesyl group to the Cys.sup.186 residue. Second, a specific protease cleaves the three carboxy-terminal amino acids. Third, the carboxylic acid terminus is methylated to a methyl ester. The farnesyl transferase enzyme (FTase) mediates the attachment of the farnesyl group to a protein. The geranylgeranyl transferase I enzyme (GGTase) mediates the attachment of the geranylgeranyl group to a protein.
Post-translational processing, particularly farnesylation, of ras proteins is critical for in vivo ras protein function. Upstream of FTase, farnesylation of a ras protein can be inhibited by mevalonate synthesis inhibitors such as lovastatin or compactin, which are HMG-CoA reductase inhibitors. Direct inhibition of FTase by short peptides or peptide-like substrates has also been demonstrated.


SUMMARY OF THE INVENTION

This invention features peptidomimetics useful in the treatment of ras-associated human cancers. The compounds of the invention inhibit post-translational modification of ras proteins by FTase, thereby down-regulating ras protein function. Substitution at the R.sup.7, R.sup.2, R.sup.4 or R.sup.5 positions (see, e.g., formula I below) modulates the specificity and selectivity of a compound of the invention for FTase and GGTase. The compounds of the invention inhibit post-translational modification of ras proteins by the related GGTase, which also results in down-regulation of ras protein function. Certain compounds of the invention are selective or specific for FTase, in preference over GGTase.
In general, the invention features a compound of the formula: ##STR1##
wherein R.sup.1 is H, NHR.sup.8, or NR.sup.8 R.sup.9, wherein R.sup.8 is H, C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.2-14 alkyloxycarbonyl or any other amino-protecting group, and R.sup.9 is C.sub.1-6 alkyl, C.sub.1-6 acyl, or C.sub.2-14 alkyloxycarbonyl; or, when taken together with R.sup.7, a bifunctional organic moiety of fewer than 50 carbon atoms; R.sup.2 is H, C.sub.1-8 alkyl, (C.sub.6-40 aryl) (C.sub.0-6 alkyl), or (C.sub.3-10 heteroaryl) (C.sub.0-6 alkyl); R.sup.3 is H, C.sub.1-6 alkyl, or (C.sub.6-40 aryl) (C.sub.0-6 alkyl); R.sup.4 is C.sub.3-16 cycloalkyl, (C.sub.3-16 heterocyclic radical)(C.sub.0-6 alkyl), (C.sub.6-12 aryl)-(C.sub.0-6 alkyl), (C.sub.3-16 heteroaryl) (C.sub.0-6 alkyl), C.sub.2-14 alkoxycarbonyl (or, where X is 2 singly-bonded H, any other amino-protecting group), R.sup.5 (CH--)(C.dbd.O)R.sup.6 R.sup.5 (CH--)(C.dbd.S)R.sup.6, R.sup.5 (CH--)(CH.sub.2)R.sup.6, or R.sup.5 (CH.sub.2 --), wherein R.sup.5 is C.sub.1-6 alkyl, (C.sub.3-10 heterocyclic radical) (C.sub.0-6 alkyl),(C.sub.

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