吉西他滨
体内
肿瘤细胞
细胞周期
癌症研究
医学
药理学
化学
生物
化疗
内科学
癌症
生物技术
作者
Lawrence M. Gelbert,Shufen Cai,Xi Lin,Concepción Sánchez‐Martínez,Miriam Del Prado,Marı́a José Lallena,Raquel Torres,Rose T. Ajamie,Graham N. Wishart,Robert Steven Flack,Blake Lee Neubauer,Jamie Young,Edward M. Chan,Philip W. Iversen,Damien M. Cronier,Emiko L. Kreklau,Alfonso de Dios
标识
DOI:10.1007/s10637-014-0120-7
摘要
The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.
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