Description
LEE011 is a cyclin-
dependent kinase (CDK) inhibitor that targets cyclin D1/CDK4 and cyclin D3/CDK6 at nanomolar concentrations. It inhibits retinoblastoma protein phosphorylation, which prevents CDK-mediated G
1-S phase transition, arresting the cell cycle in the G
1 phase, suppressing DNA synthesis, and inhibiting cancer cell growth. LEE011 has been shown to reduce proliferation in 12 of 17 human neuroblastoma-
derived cell lines by inducing cytostasis (mean IC
50 = 306 nM in sensitive lines).
Characteristics
Class: serine/threonine protein kinase
Treatment: Breast cancer
Oral bioavailability = 66%
Elimination half-life = 32 h
Protein binding = 70%
Uses
LEE 011 can be used in biological study of kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer.
Mechanism of action
Ribociclib is a dual cdk4/cdk6 inhibitor. Induces G1 phase cell cycle arrest and senescence in neuroblastoma cell lines (IC50 = 306 nM). Delays tumor growth in vivo.
Clinical Use
Protein kinase inhibitor:
Treatment of breast cancer
Clinical Use
Ribociclib was first approved in 2017 as the second CDK4/6 (cyclin-dependent kinase) inhibitor in combination with aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2?) advanced or metastatic breast cancer. In 2018, its label was expanded to pre/perimenopausal women with HR+/HER2? advanced or metastatic breast cancer.
Drug interactions
Potentially hazardous interactions with other drugs
The concomitant use of strong CYP3A4 inhibitors
including, but not limited to, the following must
be avoided: clarithromycin, indinavir, itraconazole,
ketoconazole, lopinavir, ritonavir, nefazodone,
nelfinavir, posaconazole, saquinavir, telaprevir,
telithromycin, verapamil and voriconazole.
The concomitant use of strong CYP3A4 inducers
may therefore lead to decreased exposure and
consequently a risk for lack of efficacy. The
concomitant use of strong CYP3A4 inducers should
be avoided, including, but not limited to, phenytoin,
rifampicin, carbamazepine and St John's wort.
Caution and monitoring for toxicity are advised
during concomitant treatment with sensitive
substrates of drug transporters P-gp, BCRP,
OATP1B1/1B3, OCT1, OCT2, MATE1 and
BSEP which exhibit a narrow therapeutic index,
including but not limited to digoxin, pravastatin,
rosuvastatin and metformin.
Co-administration of Kisqali with medicinal
products with a known potential to prolong the
QT interval such as anti-arrhythmic medicinal
products (including, but not limited to, amiodarone,
disopyramide, procainamide, quinidine and sotalol),
and other medicinal products that are known to
prolong the QT interval (including, but not limited
to, chloroquine, halofantrine, clarithromycin,
haloperidol, methadone, moxifloxacin, pimozide and
intravenous ondansetron) should be avoided.
Metabolism
Ribociclib is hepatically metabolised via CYP3A4 by
oxidation. Ribociclib was the main circulating drug in
plasma (44%). The major circulating metabolites included
metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803,
N-demethylation), and M1 (secondary glucuronide).
Clinical activity of ribociclib was due mainly to parent drug,
with negligible contribution from circulating metabolites.
Unchanged drug accounted for 17.3% and 12.1% of
the dose in faeces and urine, respectively. Metabolite
LEQ803 represented approximately 13.9% and 3.74%
of the administered dose in faeces and urine, respectively.
Numerous other metabolites were detected in both faeces
and urine in minor amounts (≤2.78%).
Ribociclib and its metabolites are eliminated mainly via
faeces (69.1%), with a small contribution from the renal
route (22.6%).
References
1) Rader?et al.?(2013),?Dual CDK4/6 inhibition induces cell-cycle arrest and senescence in neuroblastoma; Clin. Cancer Res.?19?6173
2) Kim?et al. (2013),?LEE011: an orally bioavailable, selective small-molecule inhibitor of CDK4/6 – reactivating Rb in cancer; Mol. Cancer Ther.?12?PR02
3) Tripathy?et al.?(2017),?Ribociclib(LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors; Clin. Cancer Res. March 28, 201
