Details

Autor(en) / Beteiligte

• Wang, Qiang
• Liu, Feiyang
• Qi, Shuang
• Qi, Ziping
• Yan, Xiao-E.
• Wang, Beilei
• Wang, Aoli
• Wang, Wei
• Chen, Cheng
• Liu, Xiaochuan
• Jiang, Zongru
• Hu, Zhenquan
• Wang, Li
• Wang, Wenchao
• Ren, Tao
• Zhang, Shanchun
• Yun, Cai-Hong
• Liu, Qingsong
• Liu, Jing

Titel

Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia

Ist Teil von

• European journal of medicinal chemistry, 2018-04, Vol.150, p.366-384

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong potency against purified PDGFRα (IC50: 132 nM) but not structurally similar PDGFRβ, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFRα revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFRα driving Chronic Eosinophilic Leukemia (CEL) cell line EOL-1 through strong blockage of PDGFRα mediated signaling pathways, arresting cell cycle progression, and induction of apoptosis. Furthermore, compound 15i effectively suppressed the EOL-1 tumor progression in the xenograft model and increased the survival rate in the engraftment tumor model. [Display omitted] •A highly selective and potent type II PDGFRα kinase inhibitor 15i was discovered.•X-ray crystal structure of PDFGRα/15i complex revealed a distinct binding feature.•15i potently inhibited the proliferation of PDGFRα driving CEL cell line EOL-1.•15i effectively suppressed the EOL-1 tumor progression in the xenograft model.