基诺美
化学
效力
药理学
生物利用度
可药性
细胞周期蛋白依赖激酶
毒性
铅化合物
细胞周期蛋白依赖激酶6
多发性骨髓瘤
药物发现
药品
激酶
体内
生物化学
体外
内科学
生物
医学
细胞周期
有机化学
生物技术
基因
细胞
作者
Kai Yuan,Wenbin Kuang,Weijiao Chen,Minghui Ji,Wenjian Min,Yasheng Zhu,Yi Hou,Xiao Wang,Jiaxing Li,Liping Wang,Peng Yang
标识
DOI:10.1016/j.ejmech.2021.114024
摘要
Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.
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