ABSTRACT
Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridones/therapeutic use , Pyrimidines/therapeutic use , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Drug Synergism , Humans , K562 Cells , Mice , Mutant Proteins/physiology , Mutation, Missense , Protein Structure, Tertiary/genetics , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/chemistry , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
Subject(s)
HIV Integrase Inhibitors/metabolism , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Microsomes, Liver/metabolism , Quinolines/metabolism , Quinolines/pharmacology , Animals , Dogs , HIV Infections/drug therapy , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacokinetics , Haplorhini , Humans , Naphthyridines/chemistry , Naphthyridines/metabolism , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several of these compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103N and/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthiosemicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.
