Abemaciclib [N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine] is an orally administered Cyclin Dependent Kinase (CDK) inhibitor, designed to block the growth of cancer cells by specifically inhibiting CDK-4 and -6. The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (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 Rb by CDK4/6, which are highly validated cancer drug targets.
In biochemical assays, Abemaciclib inhibits CDK4/cyclin D1 and CDK6/cyclin D1 with IC50 = 2 nM and 10 nM, respectively, and shows selectivity over closely related cell cycle kinases. Ki(ATP) constants were determined through kinetic studies, showing Ki(ATP) = 0.6 nM and 2.4 nM for CDK4/cyclin D1 and CDK6/cyclin D1, respectively, indicating Abemaciclib is a competitive ATP inhibitor [1].
Out of all these biochemical profiling activities, it is particularly important to observe approximately 2-3 orders of magnitude in measured IC50s in biochemical kinase selectivity against CDK1/cyclin B1, CDK2/cyclin E, and CDK7/Mat1/cyclin H. Complete lack of activity against other important cell-cycle related kinases for which inhibition could also lead to potentially confounding cell cycle arrest in G2/M such as Aurora A, B, and PLK1 was noted [1].
On Oct 2015, USFDA granted Breakthrough Therapy Designation to Abemaciclib for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer. This designation is based on data from the breast cancer of the company’s Phase I trial, JPBA, which studied the efficacy and safety of Abemaciclib in advanced or metastatic breast cancer.
In biochemical assays, Abemaciclib inhibits CDK4/cyclin D1 and CDK6/cyclin D1 with IC50 = 2 nM and 10 nM, respectively, and shows selectivity over closely related cell cycle kinases. Ki(ATP) constants were determined through kinetic studies, showing Ki(ATP) = 0.6 nM and 2.4 nM for CDK4/cyclin D1 and CDK6/cyclin D1, respectively, indicating Abemaciclib is a competitive ATP inhibitor [1].
Out of all these biochemical profiling activities, it is particularly important to observe approximately 2-3 orders of magnitude in measured IC50s in biochemical kinase selectivity against CDK1/cyclin B1, CDK2/cyclin E, and CDK7/Mat1/cyclin H. Complete lack of activity against other important cell-cycle related kinases for which inhibition could also lead to potentially confounding cell cycle arrest in G2/M such as Aurora A, B, and PLK1 was noted [1].
On Oct 2015, USFDA granted Breakthrough Therapy Designation to Abemaciclib for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer. This designation is based on data from the breast cancer of the company’s Phase I trial, JPBA, which studied the efficacy and safety of Abemaciclib in advanced or metastatic breast cancer.
Common Name: Abemaciclib
Synonyms: LY2835219; LY-2835219; LY 2835219
IUPAC Name: N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine
CAS Number: 1231929-97-7; 1231930-82-7 (mesylate)
Mechanism of Action: Kinase Inhibitor; Cyclin Dependent Kinase Inhibitor; CDK Inhibitor; CDK4 Inhibitor; CDK6 Inhibitor
Indication: Various Cancers
Development Stage: Phase I
Company: Eli Lilly
An integrated semi-mechanistic pharmacokinetic/pharmacodynamic model successfully described Abemaciclib-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing Abemaciclib plasma concentrations [2].
Abemaciclib 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 Abemaciclib 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.
Abemaciclib 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 Abemaciclib 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.
References:
1. Gelbert, T. M.; et. al. 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, 32(5), 825-837.
2. Tate, S. C.; et. al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 2014, 20(14), 3763-3774.
2. Tate, S. C.; et. al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 2014, 20(14), 3763-3774.
