Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.

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Taveras AG, Deskus J, Chao J, Vaccaro CJ, Njoroge FG, Vibulbhan B, Pinto P, Remiszewski S, del Rosario J, Doll RJ, Alvarez C, Lalwani T, Mallams AK, Rossman RR, Afonso A, Girijavallabhan VM, Ganguly AK, Pramanik B, Heimark L, Bishop WR, Wang L, Kirschmeier P, James L, Carr D, Liu M, et al.

Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.

J Med Chem. 1999 Jul 15;42(14):2651-61.

PubMed ID

10411485 [ View in PubMed

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Abstract

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Lonafarnib	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	IC 50 (nM)	1.9	N/A	N/A	Details
Lonafarnib	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	IC 50 (nM)	10	N/A	N/A	Details