Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.
Bottom Line: The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F.It also exerted strong inhibitory effects on erythropoietin-independent erythroid colonies from MPN patients and JAK2 V617F knock-in mice, where at certain doses, a preferential inhibition of JAK2 V617F mutated progenitors was detected.Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.
Affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.Show MeSH
Related in: MedlinePlus
Mentions: The JAK2/JAK1 inhibitor ruxolitinib (also known as INC424 or INCB018424) (Albany Molecular Research Inc., Albany, NY, USA) and the JAK2 inhibitor TG101348 (SYNthesis Med Chem, San Diego, CA, USA) were used. All compounds were dissolved in 100% dimethyl sulfoxide (Sigma-Aldrich, St. Louis, MO, USA) to prepare 20 mM stocks except for NVP-BEZ235, which was dissolved to prepare 10 mM stock. The identity of compounds used in this study is shown in Figure 1. All compounds were synthesized by SynMedChem except AZD6244 and XL147 (Selleck Chemicals, Houstan, TX, USA), Rapamycin and Temsirolimus (Tocris Bioscience, Bristol, UK), LY294002 from Sigma-Aldrich and SB1518 and CC401 from AMRI (Albany Molecular Research Inc.).
Affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.