Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations.

Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC50s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.

Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model.

Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.

Tuberculosis among healthcare workers in southeastern China: A retrospective study of 7-year surveillance data.

The baseline prevalence and characteristics of tuberculosis (TB) among general healthcare workers (HCWs) in southeastern China remains unknown. We conducted a retrospective study based on the TB surveillance data in Zhejiang Province from 2005 to 2011, which were extracted from the national Tuberculosis Information Management System (TIMS). We calculated and compared annual notification rates of different occupational groups and analyzed the epidemiological and clinical characteristics. The annual TB notification rates among general HCWs declined steadily from 2005 to 2011. On average, HCWs showed annual TB notification rates lower than the general population but higher than teachers. Recorded HCW TB patients averaged 35.5 years of age, with females outnumbering males (58.0% > 42.0%). The proportion of pulmonary tuberculosis (PTB) was higher among male than in the female patients (88.5% > 83.4%, P = 0.031). Our study suggested that general HCWs run a higher occupational risk than teachers although the two groups are socioeconomically comparable and that the priority should be given to the young female HCWs for TB prevention in healthcare institutions.