Correction: The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models

Kim, Sunkyu; Tiedt, Ralph; Loo, Alice; Horn, Thomas; Delach, Scott; Kovats, Steven; Haas, Kristy; Engstler, Barbara Schacher; Cao, Alexander; Pinzon-Ortiz, Maria; Mulford, Iain J.; Acker, Michael G.; Chopra, Rajiv; Brain, Christopher T.; Tomaso, Emmanuelle di; Sellers, William R.; Caponigro, Giordano

doi:10.18632/oncotarget.27407

Cited by 4 publications

(4 citation statements)

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“…In Rb-positive preclinical tumor models, ribociclib demonstrated complete dephosphorylation of Rb, in line with its mode of action as a CDK4/6 inhibitor (Fig. 1 ), as well as dose-dependent G1 cell cycle arrest and tumor regression [ 28 , 29 ]. The impact of ribociclib tumor growth reduction was also assessed by immuno-histochemistry of nuclear protein Ki67 (Ki67) [ 30 ], a nuclear marker of active cell proliferation in normal and tumor cell populations [ 31 ].…”

Section: Biopharmaceutical Properties and Preclinical Pharmacologymentioning

confidence: 93%

“…Ribociclib is a highly selective dual inhibitor of the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes, with 50% inhibitory concentrations (IC 50 ) of 0.01 μM and 0.039 μM, respectively [ 28 , 29 ]. Inhibition of these complexes is mediated by binding of ribociclib to the ATP cleft of the CDK4 and CDK6 kinases [ 10 ].…”

Section: Biopharmaceutical Properties and Preclinical Pharmacologymentioning

confidence: 99%

“…In mouse xenograft models derived from CDK4/6-overexpressing cell-lines, ribociclib treatment resulted in reduced Ki67 staining and impaired cell proliferation, together with diminished Rb phosphorylation [ 30 ]. In a preclinical study of 50 breast cancer cell lines, ribociclib demonstrated inhibitory activity predominantly against ER+ cell lines, suggesting that ER+ breast cancer cells might be particularly susceptible to CDK4/6 inhibition [ 10 ], and in four mouse xenograft models of HR+ breast cancer, significant tumor growth inhibition was observed with single-agent ribociclib [ 28 , 29 , 32 ]. The addition of letrozole or fulvestrant to ribociclib further increased the tumor growth inhibition compared with single agent in mouse xenograft models of HR+ breast cancer [ 28 , 29 , 32 ].…”

Section: Biopharmaceutical Properties and Preclinical Pharmacologymentioning

confidence: 99%

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Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer

Ji,

Schiller,

Yang

et al. 2024

Clin Pharmacokinet

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Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2−) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4 h, mean half-life of 32.0 h and oral bioavailability of 65.8% at 600 mg. It is eliminated mainly by hepatic metabolism (~ 84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600 mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600 mg QD starting dose, with potential individualized dose reductions to 400 mg and 200 mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2− ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01338-z.

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Section: Biopharmaceutical Properties and Preclinical Pharmacologymentioning

confidence: 93%

Section: Biopharmaceutical Properties and Preclinical Pharmacologymentioning

confidence: 99%

Section: Biopharmaceutical Properties and Preclinical Pharmacologymentioning

confidence: 99%

See 1 more Smart Citation

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer

Ji,

Schiller,

Yang

et al. 2024

Clin Pharmacokinet

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“…Palbociclib (Ibrance ® ) ( 8 ) [ 237 , 238 ], ribociclib (Kisqali ® ) (Ribotix ® ) ( 9 ) [ 239 , 240 , 241 ], and abemaciclib (Verzenio ® ) ( 10 ) [ 242 ] are FDA-approved CDK4/CDK6 inhibitors that are used therapeutically for breast cancer [ 37 , 243 ]. Biological studies showed that 8 suppresses HIV-1 (EC 50 = 0.016 μM) and HSV-1 (EC 50 = 0.020 μM) proliferation in vitro [ 244 ].…”

Section: Kinases Inhibitors In Various Developmental Stages As Antivi...mentioning

confidence: 99%

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Hajjo

Sabbah

Abusara

et al. 2023

Viruses

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Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

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Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation

Amin

El‐Saadi

Abdel-Fattah

et al. 2023

Bioorganic Chemistry

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Correction: The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models

Cited by 4 publications

References 0 publications

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation

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