193275-84-2 Usage
Description
Lonafarnib, also known as SCH66336, is a farnesyl transferase inhibitor (FTI) that targets Kand N-Ras, which are substrates of farnesyl transferase. It is 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-oxoethylpiperidine-1-carboxamide with R configuration. Lonafarnib is an orally bioavailable tricyclic compound that inhibits farnesyl protein transferase, Rheb farnesylation, and mTOR signaling, enhancing the antitumor activity of taxane and tamoxifen. It induces CCAAT/enhancer-binding protein homologous protein-dependent expression of death receptor 5, leading to the induction of apoptosis in human cancer cells.
Uses
Used in Chemotherapeutic Applications:
Lonafarnib is used as a chemotherapeutic agent, specifically as a farnesyl transferase inhibitor. It plays a crucial role in the treatment of various types of cancer by inhibiting the farnesylation process, which is essential for the activation of certain oncogenes, such as Kand N-Ras.
Used in Cancer Treatment:
Lonafarnib is used as an anticancer agent for the treatment of various types of cancer. It inhibits the farnesyl protein transferase enzyme, which is involved in the post-translational modification of proteins, including oncogenes. This inhibition leads to the suppression of tumor growth and progression.
Used in Enhancing Antitumor Activity:
Lonafarnib is used to enhance the antitumor activity of other chemotherapeutic drugs, such as taxane and tamoxifen. By inhibiting farnesyl protein transferase, it can increase the effectiveness of these drugs in treating cancer.
Used in Inducing Apoptosis in Cancer Cells:
Lonafarnib is used to induce apoptosis in human cancer cells. It does so by inducing the expression of death receptor 5 through the activation of CCAAT/enhancer-binding protein homologous protein. This leads to the programmed cell death of cancer cells, which is a desirable outcome in cancer treatment.
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
vomitingdiarrheanauseastomach painconstipationgasdecreased appetitedecreased weight
Check Digit Verification of cas no
The CAS Registry Mumber 193275-84-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,9,3,2,7 and 5 respectively; the second part has 2 digits, 8 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 193275-84:
(8*1)+(7*9)+(6*3)+(5*2)+(4*7)+(3*5)+(2*8)+(1*4)=162
162 % 10 = 2
So 193275-84-2 is a valid CAS Registry Number.
InChI:InChI=1/C27H31Br2ClN4O2/c28-20-12-19-2-1-18-13-21(30)14-22(29)24(18)25(26(19)32-15-20)17-5-9-33(10-6-17)23(35)11-16-3-7-34(8-4-16)27(31)36/h12-17,25H,1-11H2,(H2,31,36)/t25-/m1/s1
193275-84-2Relevant articles and documents
(+)-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
George Njoroge,Taveras, Arthur G.,Kelly, Joseph,Remiszewski, Stacy,Mallams, Alan K.,Wolin, Ronald,Afonso, Adriano,Cooper, Alan B.,Rane, Dinananth F.,Liu, Yi-Tsung,Wong, Jesse,Vibulbhan, Bancha,Pinto, Patrick,Deskus, Jeffrey,Alvarez, Carmen S.,Del Rosario, Joycelyn,Connolly, Michael,Wang, James,Desai, Jagdish,Rossman, Randall R.,Robert Bishop,Patton, Robert,Wang, Lynn,Kirschmeier, Paul,Bryant, Mathew S.,Nomeir, Amin A.,Lin,Liu, Ming,McPhail, Andrew T.,Doll, Ronald J.,Girijavallabhan, Viyyoor M.,Ganguly, Ashit K.
, p. 4890 - 4902 (1998)
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.
A novel enantioselective alkylation and its application to the synthesis of an anticancer agent
Kuo, Shen-Chun,Chen, Frank,Hou, Donald,Kim-Meade, Agnes,Bernard, Charles,Liu, Jinchu,Levy, Stacy,Wu, George G.
, p. 4984 - 4987 (2007/10/03)
A novel enantioselective alkylation of double benzylic substrates with secondary electrophiles is reported. A simple norephedrine-based chiral ligand was synthesized that gives alkylation product in 95% yield and 95% ee. A unique water effect on the enantioselectivity was unveiled. Good to excellent ee values were obtained with a number of double benzylic substrates and secondary electrophiles. This novel reaction has been applied to the synthesis of a promising anticancer agent.