LONAFARNIB

Uses

Chemotherapeutic (farnesyl transfer ase inhibitor).

Uses

Lonafarnib is an orally bioavailable tricyclic inhibitor of farnesyl protein transferase. It inhibits Rheb farnesylation and mTOR signaling and enhances taxane and tamoxifen antitumor activity. Studies show that it induces CCAAT/enhancer-binding protein homologous protein-dependent expression of death receptor 5, leading to induction of apoptosis in human cancer cells

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.

General Description

Lonafarnib (SCH66336) is a farnesyl transferase inhibitor (FTI). K- and N-Ras are substrates of farnesyl transferase.

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.

Side effects

• vomiting
• diarrhea
• nausea
• stomach pain
• constipation
• gas
• decreased appetite
• decreased weight

Synthesis

The two benzylic protons of tricyclic compound 177 were removed in the presence of quinine and mesylate 180 to generate intermediate 181 with excellent conversion and 95% enantiomeric purity (ee). In situ removal of the Boc protecting group under acidic conditions allowed 181 to crystallize as N-acetyl-L-phenylalaninate 182, which was isolated from 177 in 80% yield, further increasing the yield to 99%. N-Boc piperidine acetic acid 183 was coupled to 182 under conventional amide bond formation conditions. Subsequent removal of the Boc protecting group and urea bond formation using N-methylpyrrolidone (NMP) and urea ultimately afforded lonafarnib (XXIV).

target

FT

storage

Store at -20°C