Definition
ChEBI: A 4-{2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl}piperidine-1-carboxamide that has R configuration. It is used as oral farnesyltransferase
nhibitor.
Biological Activity
lonafarnib (sch66336, sarasar) is an potent, selective, orally, bioavailable tricyclic nonpeptidyl nonsulfhydry inhibitor of farnesyltransferase (ftase).[1] it is a small molecular with the formula of c27h31br2cln4o2 and molecular weight of 638.82. farnesylated ras proteins was found to regulate signal transduction pathways which drive cell proliferation, growth and survival and be required for its membrane localization.[1, 2] lonafarnib inhibits the post-translational farnesylcation of ras proteins, therefore blocking translocation of ras to the plasma membrane.[3][1] eric w, malcolm j. m, kim n. c, d. scott e, et al. a multinomial phase ii study of lonafarnib (sch 66336) in patients with refractory urothelial cancer. urologic oncology: seminars and original investigations. 2005, 23. 143-149.[2] gongjie l, stacey a. t, cindy h. m, yunsheng h, w. robert b, et al. continuous and intermittent dosing of lonafarnib potentiates the therapeutic efficacy of docetaxel on preclinical human prostate cancer models. int. j. cancer. 2009, 125. 2711–2720.[3] vasiliki a. n, alexander j. s, keith t. f, hensin t, et al. melanoma: new insights and new therapies. j invest dermatol. 2012, 132. 854–863.
Biochem/physiol Actions
Lonafarnib prevents the post-translational lipid modification of H-Ras and other farnesylated proteins. Lonafarnib treatment results in microtubule bundling, increased microtubule acetylation and stabilization and suppression of microtubule dynamics.
Mechanism of action
Lonafarnib is a protein farnesyltransferase inhibitor (FTI) that reversibly binds to the farnesyltransferase CAAX binding site9, thereby inhibiting progerin farnesylation and subsequent intercalation into the nuclear membrane.
