ABSTRACT
A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5-pyrazolylamine scaffold. The structure-activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells.
Subject(s)
Amines/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Amines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzenesulfonates/chemistry , Benzenesulfonates/pharmacology , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indazoles/chemistry , Indazoles/pharmacology , Mice , Molecular Structure , Niacinamide/analogs & derivatives , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Sorafenib , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Limited structural information of drug targets, cellular toxicity possessed by lead compounds, and large amounts of potential leads are the major issues facing the design-oriented approach of discovering new leads. In an attempt to tackle these issues, we have developed a process of virtual screening based on the observation that conformational rearrangements of the dengue virus envelope protein are essential for the mediation of viral entry into host cells via membrane fusion. Screening was based solely on the structural information of the Dengue virus envelope protein and was focused on a target site that is presumably important for the conformational rearrangements necessary for viral entry. To circumvent the issue of lead compound toxicity, we performed screening based on molecular docking using structural databases of medical compounds. To enhance the identification of hits, we further categorized and selected candidates according to their novel structural characteristics. Finally, the selected candidates were subjected to a biological validation assay to assess inhibition of Dengue virus propagation in mammalian host cells using a plaque formation assay. Among the 10 compounds examined, rolitetracycline and doxycycline significantly inhibited plaque formation, demonstrating their inhibitory effect on dengue virus propagation. Both compounds were tetracycline derivatives with IC(50)s estimated to be 67.1 microM and 55.6 microM, respectively. Their docked conformations displayed common hydrophobic interactions with critical residues that affected membrane fusion during viral entry. These interactions will therefore position the tetracyclic ring moieties of both inhibitors to bind firmly to the target and, subsequently, disrupt conformational rearrangement and block viral entry. This process can be applied to other drug targets in which conformational rearrangement is critical to function.
