LEE011

LEE011 is an ATP-competitive and orally active CDK4/6 inhibitor with IC50 values of 10nM and 39nM^[1]. LEE011 inhibits the phosphorylation of retinoblastoma protein, thereby preventing CDK-mediated G1-S phase transition, causing cell cycle arrest in the G1 phase, inhibiting DNA synthesis, and suppressing cancer cell growth ^[2]. LEE011 is commonly used in targeted therapy research for hormone receptor-positive breast cancer and other solid tumors ^[3].

In three leukemia cell lines, MV4-11, HL-60, and NB4, LEE011(2-5μM;72-48h) significantly induced G1 phase cell cycle arrest in acute leukemia cells ^[4]. In neuroendocrine tumor cell lines (BON1, QGP1, NCI-H727, and GOT1), LEE011 (500nM; 72h) protects NET cells from DNA damage-induced apoptosis by blocking PARP cleavage and caspase-3/7 activity ^[5].

In the JeKo-1 xenograft model in nude mice, LEE011 (30-125mg/kg; po; 5d) induces robust inhibition of tumor growth in vivo, concomitant with on-target myelosuppression ^[6]. In the MOLT4 orthotopic mouse model, LEE011 (75mg/kg; po; 5d) showed a decrease in spleen weight after 5 days of treatment ^[7]. In patient-derived human liposarcoma xenograft models, oral administration of LEE011(250mg/kg; po; 21d) to mice bearing human liposarcoma xenografts resulted in an approximately 50% reduction in tumor uptake of ¹⁸F-fluorodeoxyglucose, accompanied by a decrease in tumor biomarkers (including RB phosphorylation and bromodeoxyuridine incorporation). Sustained treatment with LEE011 suppresses tumor growth or induces tumor regression while showing no adverse impact on body weight in mice. Following prolonged continuous administration, restoration of RB phosphorylation and cell cycle progression was observed ^[8].

References:
[1]. VanArsdale T, Boshoff C, Arndt K T, et al. Molecular pathways: targeting the cyclin D–CDK4/6 axis for cancer treatment[J]. Clinical cancer research, 2015, 21(13): 2905-2910.
[2]. Dickson M A. Molecular pathways: CDK4 inhibitors for cancer therapy[J]. Clinical cancer research, 2014, 20(13): 3379-3383.
[3]. Juric D, Munster P N, Campone M, et al. Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+), HER2-negative (HER2–) advanced breast cancer (aBC): Phase Ib safety, preliminary efficacy and molecular analysis[J]. 2016.
[4].Tao Y F, Wang N N, Xu L X, et al. Molecular mechanism of G1 arrest and cellular senescence induced by LEE011, a novel CDK4/CDK6 inhibitor, in leukemia cells[J]. Cancer cell international, 2017, 17(1): 35.
[5]. Aristizabal Prada E T, Nölting S, Spoettl G, et al. The novel cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) alone and in dual-targeting approaches demonstrates antitumoral efficacy in neuroendocrine tumors in vitro[J]. Neuroendocrinology, 2017, 106(1): 58-73.
[6]. Kim S, Tiedt R, Loo A, et al. The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models[J]. Oncotarget, 2018, 9(81): 35226.
[7]. Pikman Y, Alexe G, Roti G, et al. Synergistic drug combinations with a CDK4/6 inhibitor in T-cell acute lymphoblastic leukemia[J]. Clinical Cancer Research, 2017, 23(4): 1012-1024.
[8]. Zhang Y X, Sicinska E, Czaplinski J T, et al. Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo[J]. Molecular cancer therapeutics, 2014, 13(9): 2184-2193.

LEE011是一种具有口服活性的特异性细胞周期蛋白依赖性激酶CDK4/6抑制剂。LEE011以纳摩尔浓度靶向cyclin D1/CDK4和cyclin D3/CDK6^[1]。LEE011通过抑制视网膜母细胞瘤蛋白的磷酸化，阻断CDK介导的G1-S期进程转换，从而导致细胞周期停滞在G1期，抑制DNA合成和癌细胞生长^[2]。LEE011通常用于激素受体阳性乳腺癌及其他实体瘤的靶向治疗研究^[3]。

在三种白血病细胞系（MV4-11、HL-60和NB4）中，LEE011（2-5μM；48-72h）能显著诱导急性白血病细胞发生G1期细胞周期阻滞^[4]。在神经内分泌肿瘤细胞系（BON1、QGP1、NCI-H727和GOT1）中，LEE011（500nM；72h）可通过阻断PARP裂解和caspase-3/7活性，保护细胞NET免受DNA损伤诱导型 ^[5]。

在JeKo-1裸鼠异种移植模型中，LEE011（30-125mg/kg；po；5d）可在体内强效抑制肿瘤生长，并伴随靶向相关的骨髓抑制^[6]。在MOLT4原位小鼠模型中，LEE011（75mg/kg；po；5d）治疗5天后可观察到脾脏重量下降^[7]。在患者来源的人源脂肪肉瘤异种移植模型中，对荷瘤小鼠口服LEE011（250mg/kg；po；21d）可使肿瘤对¹⁸F-氟代脱氧葡萄糖的摄取减少约50%，并伴有肿瘤生物标志物（包括RB蛋白磷酸化和溴脱氧尿苷掺入）的下降。LEE011持续治疗可抑制肿瘤生长或诱导肿瘤消退，且未对小鼠体重产生不良影响。在长期持续给药后，可观察到RB蛋白磷酸化和细胞周期进程恢复正常^[8]。