Brasca Maria Gabriella, Nesi Marcella, Avanzi Nilla, Ballinari Dario, Bandiera Tiziano, Bertrand Jay, Bindi Simona, Canevari Giulia, Carenzi Davide, Casero Daniele, Ceriani Lucio, Ciomei Marina, Cirla Alessandra, Colombo Maristella, Cribioli Sabrina, Cristiani Cinzia, Della Vedova Franco, Fachin Gabriele, Fasolini Marina, Felder Eduard R, Galvani Arturo, Isacchi Antonella, Mirizzi Danilo, Motto Ilaria, Panzeri Achille, Pesenti Enrico, Vianello Paola, Gnocchi Paola, Donati Daniele
Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
Bioorg Med Chem. 2014 Sep 1;22(17):4998-5012. doi: 10.1016/j.bmc.2014.06.025. Epub 2014 Jun 21.
We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
我们在此报告一类新型JAK2抑制剂的发现、基于结构的设计、合成及生物学评价。对该系列化合物的优化导致了强效且口服生物利用度良好的JAK2抑制剂28（NMS-P953）的鉴定。化合物28在SET-2异种移植肿瘤模型中显示出显著的肿瘤生长抑制作用，其作用机制通过已知生物标志物的典型体内调节得以证实，并且具有良好的药代动力学和安全性特征。
