(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336):  A Very Potent Farnesyl Protein Transferase Inhibitor as a Novel Antitumor Agent

Abstract

We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia

“…26,31 This compound has been described in detail elsewhere. [32][33][34] SCH66336 was received in lyophilized form, reconstituted in dimethyl sulfoxide (DMSO), and maintained at Ϫ20°C. For experiments in tissue culture, SCH66336 was diluted at least 1:500 in appropriate tissue culture media before it was added to in vitro assays.…”

Farnesyltransferase Inhibitor SCH66336 Induces Rapid Phosphorylation of Eukaryotic Translation Elongation Factor 2 in Head and Neck Squamous Cell Carcinoma Cells

“…This FTI has also been shown to have antitumor activity in vitro and in vivo for other tumors with or without a ras mutation (14,15). However, the mechanism of this activity is poorly understood.…”

Protein Farnesyltransferase Inhibitor (SCH 66336) Abolishes NF-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli Leading to Suppression of NF-κB-regulated Gene Expression and Up-regulation of Apoptosis

“…The SCH 66336 ((ϩ)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5, 6)-cyclohepta[1,2-b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide), a potent nonpeptide tricyclic FTI (11), is one of the first to undergo clinical testing (12). In vitro, SCH 66336 inhibits the anchorage-independent growth of many human tumor lines irrespective of the activation status of the ras oncogene (13,14).…”