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.