title: Synthesis, structure-activity relationship, and p210(bcr-abl) protein tyrosine kinase activity of novel AG 957 analogs.
abstract: A series of novel, sterically hindered lipophilic analogs of AG 957 was designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. The in vitro activity, in vivo anti-leukemia activity, and pharmacology of these PTK inhibitors were studied. Some aspects of the structure-activity relationship associated with the carboxylic acid, phenol ring, and linker modifications are discussed. We have demonstrated that the 1,4-hydroquinone moiety is essential for activity and that sterically hindered esters contribute to enhanced in vivo efficacy. Adaphostin (NSC 680410) has emerged as the improved compound with the maximum in vivo anti-leukemia hollow fiber activity, concordant with the original lead compound AG 957. Currently, adaphostin is undergoing preclinical toxicology studies.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Gurmeet
authors.initials: G
authors.lastname: Kaur
authors.forename: Ven L
authors.initials: VL
authors.lastname: Narayanan
authors.forename: Prabhakar A
authors.initials: PA
authors.lastname: Risbood
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Hollingshead
authors.forename: Sherman F
authors.initials: SF
authors.lastname: Stinson
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Varma
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020032:Tyrphostins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020032:Tyrphostins; C104965:tyrphostin AG957; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl