Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)
ABSTRACT 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.
- SourceAvailable from: Stephen J Smerdon[Show abstract] [Hide abstract]
ABSTRACT: A high-throughput screen against PknB, an essential serine-threonine protein kinase present in Mycobacterium tuberculosis (M. tuberculosis), allowed the identification of an aminoquinazoline inhibitor which was used as a starting point for SAR investigations. Although a significant improvement in enzyme affinity was achieved, the aminoquinazolines showed little or no cellular activity against M. tuberculosis. However, switching to an aminopyrimidine core scaffold and the introduction of a basic amine side chain afforded compounds with nanomolar enzyme binding affinity and micromolar minimum inhibitory concentrations against M. tuberculosis. Replacement of the pyrazole head group with pyridine then allowed equipotent compounds with improved selectivity against a human kinase panel to be obtained.Bioorganic & medicinal chemistry letters 03/2012; 22(9):3349-53. DOI:10.1016/j.bmcl.2012.02.107 · 2.42 Impact Factor
- [Show abstract] [Hide abstract]
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. (C) 2012 Published by Elsevier Ltd.Bioorganic & medicinal chemistry letters 07/2012; 22(14):4654-9. DOI:10.1016/j.bmcl.2012.05.116 · 2.42 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure-activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia.Bioorganic & medicinal chemistry 04/2013; 21(11). DOI:10.1016/j.bmc.2013.03.083 · 2.79 Impact Factor