LY2835219

LY2835219 free base is a potent and selective inhibitor of CDK4 and CDK6 with IC₅₀ of 2nM and 10nM in cell-free assays, respectively^[1].

LY2835219 free base (0.001-10μM; 24h) inhibited p-Rb in a concentration-dependent manner, resulting in cell arrest in the G1 phase (2 N DNA content) and a decrease in cell number due to inhibition of proliferation. LY2835219 free base 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^[2]. LY2835219 free base (0.1, 0.2 and 0.4μM; 24h) potentiated the cytotoxicity of conventional chemotherapeutic agents in ABCB1 and ABCG2-overexpressing cells^[3].

LY2835219 free base (50mg/kg; po; 56d) was effective and well tolerated in mice bearing Colo-205 xenograft tumors. After administration for up to 56days, there was no significant weight loss in mice and no significant tumor growth^[2]. LY2835219 free base (45mg/kg; po; 14d) combined with RAD001 had a synergistic anti-tumor effect on HNSCC xenograft tumors[4].

References:
[1].Corona SP, Generali D. Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer. Drug Des Devel Ther. 2018 Feb 16;12:321-330.
[2]. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37.
[3]Wu T, Chen Z, To KKW, Fang X, Wang F, Cheng B, Fu L. Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2017 Jan 15;124:29-42.
[4]. Ku BM, Yi SY, Koh J, Bae YH, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget. 2016 Mar 22;7(12):14803-13.

LY2835219 free base是 CDK4 和 CDK6 的强效选择性抑制剂，在非细胞实验中的 IC₅₀ 分别为 2nM 和 10nM^[1]。

LY2835219 free base（0.001-10μM，24h）以浓度依赖性方式抑制 p-Rb，导致细胞停滞在 G1 期（2 N DNA 含量），细胞数量因增殖受抑制而减少。LY2835219 free base以低纳摩尔的效价抑制 CDK4 和 CDK6，抑制 Rb 磷酸化，导致 G1 期停滞和增殖抑制，其活性对 Rb 细胞具有特异性^[2]。LY2835219 free base（0.1、0.2 和 0.4μM；24h）可增强传统化疗药物对 ABCB1 和 ABCG2 基因敲除细胞的细胞毒性^[3]。

LY2835219 free base （50mg/kg；po；56d）对 Colo-205 异种移植肿瘤小鼠有效且耐受性良好，给药长达 56 天，小鼠体重无明显下降，肿瘤无明显生长^[2]。LY2835219 free base（45mg/kg；po；14d）与 RAD001 联用对 HNSCC 异种移植瘤有协同抗肿瘤作用^[4]。