Joanne M. Petrin

Discovery of novel nonpeptide tricyclic inhibitors of ras farnesyl protein transferase

A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been undertaken. The discovery of compounds that are potent FPT inhibitors in the nanomolar range has been achieved. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit farnesyl protein transferase (FPT) and not geranylgeranyl protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in Cos monkey kidney cells.

Inhibition of protein kinase c by the tyrosine kinase inhibitor erbstatin

We examined the tyrosine kinase inhibitor erbstatin and several derivatives for their ability to inhibit serine/threonine protein kinases in vitro. Erbstatin was found to inhibit protein kinase C (PKC) with an IC50 of 19.8 +/- 3.2 microM. A trihydroxy derivative of erbstatin inhibited PKC with similar potency, whereas the corresponding methoxy derivatives were inactive. Inhibition by erbstatin was competitive with ATP (Ki = 11.0 +/- 2.3 microM) and non-competitive with the phosphate acceptor, either histone or the synthetic peptide kemptide. Action of erbstatin at the catalytic site of PKC was further indicated by the findings that it inhibited the catalytic fragment of PKC but did not inhibit the interaction of phorbol ester with the intact enzyme. Erbstatin had a similar potency against three PKC isozymes (alpha, beta, and gamma) examined. In addition, erbstatin was found to inhibit other serine/threonine kinases (assayed at their Km for ATP). The greatest potency was observed versus the cyclic nucleotide-dependent kinases, while lower potency was seen versus myosin light chain kinase. These observations are discussed in terms of the structure and kinetic properties of PKC and the epidermal growth factor receptor tyrosine kinase.

A cembranolide diterpene farnesyl protein transferase inhibitor from the marine soft coral Lobophytum cristagalli

Abstract A previously described cembranolide diterpene from Lobophytum cristagalli was identified as a potent (IC50 0.15 μM) inhibitor of farnesyl protein transferase (FPT). The compound showed selectivity for FPT as compared to the closely related enzyme geranylgeranyl protein transferase-1 (IC50 5.3 μM). Kinetic evaluation suggests that this compound competes with the protein/peptide farnesyl acceptor substrate, and not with farnesyl pyrophosphate for inhibition of FPT.

Antitumor 8-chlorobenzocycloheptapyridines: a new class of selective, nonpeptidic, nonsulfhydryl inhibitors of ras farnesylation.

Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor.

NOVEL TRICYCLIC AMINOACETYL AND SULFONAMIDE INHIBITORS OF RAS FARNESYL PROTEIN TRANSFERASE

Abstract Novel tricyclic FPT inhibitors with submicromolar FPT activity are described. Greatly enhanced FPT activity is realized with phthaloyl derivatized amino compound 2k, which showed FPT inhibitory activity of IC50 = 0.66 μM. Sulfonamides 5g and 50 were also found to be potent FPT inhibitor. SAR resulting from a variety of tricyclic amino acids and sulfonamide derivatives is discussed.

Indolocarbazoles. 1. Total synthesis and protein kinase inhibiting characteristics of compounds related to K-252c.

Abstract The condensation of indolo[2,3-a]-carbazole ( 12 ) with 2,5-dimethoxytetrahydrofuran derivatives gave cyclofuranosylated compounds (e.g. 13 ), which were converted via dibromocompounds to the dinitriles (e.g. 25 ). Hydrolysis, hydrolysis-reduction and thiolysis afforded imides, lactams (e.g. 27 ) and their thio analogs. These compounds were potent inhibitors of the protein kinase C family.