Abstract
Lometrexol, a tight-binding antifolate inhibitor of the purine de novo enzyme glycinamide ribonucleotide formyltransferase (GARFT), was the first GARFT inhibitor to be investigated clinically. Unexpected observations of delayed cumulative toxicity prompted a search for a second generation antimetabolite with a more favorable biochemical, pharmacological and toxicological profile. LY309887, 6R-2',5'-thienyl-5, 10-dideazatetrahydrofolic acid, had 9-fold greater potency to inhibit GARFT (Ki = 6.5 nM) compared to lometrexol. Like lometrexol, LY309887 was activated by folpolyglutamate synthetase, however, it had a lower first order rate constant. In vitro and in vivo data were consistent with these observations: polyglutamation of LY309887 was less extensive compared to lometrexol and livers of mice accumulated fewer polyglutamates of LY309887 than polyglutamates of lometrexol. The affinities of these two compounds for isoforms of human folate receptors (FR) were compared. Lometrexol had a 6-fold higher affinity for FR alpha than LY309887 and both compounds had higher affinity for the alpha isoform compared to the beta isoform. The selectivity of LY309887 for FR alpha (beta (Ki)/ alpha (Ki) = 10.5) was twice that of lometrexol's (be...Continue Reading
References
Nov 3, 1992·Biochemical Pharmacology·X WangM Ratnam
May 8, 1992·Biochemical Pharmacology·W H WardA L Jackman
Aug 1, 1990·Investigational New Drugs·J F WorzallaG B Grindey
Jul 1, 1985·Journal of Medicinal Chemistry·E C TaylorR G Moran
Sep 1, 1982·British Journal of Cancer·A M SalehJ Walters
Aug 11, 1981·Molecular and Cellular Biochemistry·J J McGuire, J R Bertino
Nov 17, 1993·Journal of Chromatography·J R MuindiC Shih
May 1, 1994·Cancer·J F RossM Ratnam
Jan 20, 1995·Journal of Chromatography. B, Biomedical Applications·S R WedgeD R Newell
Jul 21, 1993·Journal of the National Cancer Institute·M S RayR G Moran
Jan 1, 1996·Advances in Enzyme Regulation·L G MendelsohnG B Grindey
Jan 1, 1996·Investigational New Drugs·S LaohavinijA H Calvert
Citations
Dec 29, 2005·Investigational New Drugs·Jackie Walling
Mar 31, 2000·Pharmacology & Therapeutics·A RosowskyR A Forsch
Feb 17, 1999·Bioorganic & Medicinal Chemistry Letters·L S GossettC Shih
Aug 9, 2008·Journal of Medicinal Chemistry·Jessica K DeMartinoDale L Boger
Dec 29, 2009·Bioorganic & Medicinal Chemistry·Xiang Ma, Wai-Keung Chui
Nov 22, 2008·Archives of Biochemistry and Biophysics·Martha S FieldPatrick J Stover
Feb 10, 1999·Biochemical Pharmacology·H M FaesselW R Greco
Mar 29, 2001·Biochemical Pharmacology·R ZhaoI D Goldman
Oct 27, 1999·Biochemical Pharmacology·R ZhaoI D Goldman
Dec 15, 2005·Journal of Theoretical Biology·Yehuda G AssarafRon Y Pinter
Nov 10, 2006·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·G Jansen, R Pieters
Apr 26, 2005·Bioorganic & Medicinal Chemistry·Youhoon ChongDale L Boger
Feb 28, 2001·Biochemical Pharmacology·E MarshmanN J Curtin
Dec 21, 2002·International Journal of Cancer. Journal International Du Cancer·Esti LianiYehuda G Assaraf
Jun 9, 2017·Microorganisms·Jessica L Chitty, James A Fraser
Jun 1, 2017·The Journal of Biological Chemistry·Jessica L ChittyJames A Fraser
May 28, 2019·FEBS Letters·Emma ScalettiPål Stenmark
Jun 28, 2001·Oncogene·J Adams, P J Elliott
Jun 17, 2000·The Journal of Biological Chemistry·R ZhaoI D Goldman
Jan 8, 2017·The Journal of Biological Chemistry·Jessica L ChittyJames A Fraser
Sep 24, 2015·Oncotarget·Theodora StivarouIlaria Marzi
Dec 1, 2018·Archives of Toxicology·M VidmarM Sollner Dolenc
Feb 12, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Davinder S Theti, Ann L Jackman
Nov 20, 2002·Accounts of Chemical Research·Richard I ChristophersonPaul K Wilson
Sep 18, 2003·Bioorganic & Medicinal Chemistry·Joel DesharnaisDale L Boger
Sep 17, 2004·Journal of Medicinal Chemistry·Nicola J CurtinRoger J Griffin