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Ribociclib

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https://www.readbyqxmd.com/read/29153893/selective-atp-competitive-leads-of-cdk4-discovery-by-3d-qsar-pharmacophore-mapping-and-molecular-docking-approach
#1
Rohini Rondla, Lavanya Souda PadmaRao, Vishwanath Ramatenki, Aboubakr Haredi-Abdel-Monsef, Sarita Rajender Potlapally, Uma Vuruputuri
The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val(96), Arg(101), and Glu(144) residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib...
November 14, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29134635/ribociclib-bioavailability-is-not-affected-by-gastric-ph-changes-or-food-intake-in-silico-and-clinical-evaluations
#2
Tanay S Samant, Shyeilla Dhuria, Yasong Lu, Marc Laisney, Shu Yang, Arnaud Grandeury, Martin Mueller-Zsigmondy, Kenichi Umehara, Felix Huth, Michelle Miller, Caroline Germa, Mohamed Elmeliegy
Ribociclib (KISQALI®), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using (1) biorelevant media solubility, (2) physiologically based pharmacokinetic (PBPK) modeling, (3) non-compartmental analysis (NCA) of clinical trial data, and (4) population PK (PopPK) analysis...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29133594/competitive-kinase-enrichment-proteomics-reveals-that-abemaciclib-inhibits-gsk3%C3%AE-and-activates-wnt-signaling
#3
Emily M Cousins, Dennis Goldfarb, Feng Yan, Jose Roques, David B Darr, Gary L Johnson, Michael B Major
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29125603/cell-cycle-arrest-through-indirect-transcriptional-repression-by-p53-i-have-a-dream
#4
REVIEW
Kurt Engeland
Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements...
November 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29119080/metastatic-breast-cancer-endocrine-therapy-landscape-reshaped
#5
REVIEW
Mohamad Adham Salkeni, Samantha June Hall
Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus...
October 2017: Avicenna Journal of Medicine
https://www.readbyqxmd.com/read/29103175/efficacy-and-safety-in-older-patient-subsets-in-studies-of-endocrine-monotherapy-versus-combination-therapy-in-patients-with-hr-her2-%C3%A2-advanced-breast-cancer-a-review
#6
REVIEW
Rachel A Freedman, Sara M Tolaney
PURPOSE: Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population. METHODS: We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with ET ± targeted agents...
November 4, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29097609/recent-advances-of-cell-cycle-inhibitor-therapies-for-pediatric-cancer
#7
REVIEW
Christopher C Mills, E A Kolb, Valerie B Sampson
This review describes the pivotal roles of cell-cycle and checkpoint regulators and discusses development of specific cell-cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib), and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the cross-talk of signals activated by cell-cycle arrest, as well as pediatric-focused drug development, are critical for the advancement of drugs for rare childhood diseases...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29059492/a-phase-1-study-of-single-agent-ribociclib-in-japanese-patients-with-advanced%C3%A2-solid%C3%A2-tumors
#8
Toshihiko Doi, Becker Hewes, Tomoyuki Kakizume, Takeshi Tajima, Norifumi Ishikawa, Yasuhide Yamada
The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, demonstrated preliminary clinical activity in a phase 1 study in the United States and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed...
October 23, 2017: Cancer Science
https://www.readbyqxmd.com/read/29058175/ribociclib-with-letrozole-vs-letrozole-alone-in-elderly-patients-with-hormone-receptor-positive-her2-negative-breast-cancer-in-the-randomized-monaleesa-2-trial
#9
Gabe S Sonke, Lowell L Hart, Mario Campone, Frans Erdkamp, Wolfgang Janni, Sunil Verma, Cristian Villanueva, Erik Jakobsen, Emilio Alba, Erik Wist, Anne M Favret, Thomas Bachelot, Roberto Hegg, Paul Wheatley-Price, Farida Souami, Santosh Sutradhar, Michelle Miller, Caroline Germa, Howard A Burris
PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2- advanced breast cancer. METHODS: 668 postmenopausal women with HR+, HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase II MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation...
October 22, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29039822/ribociclib-kisqali-for-advanced-or-metastatic-breast-cancer
#10
(no author information available yet)
No abstract text is available yet for this article.
October 23, 2017: Medical Letter on Drugs and Therapeutics
https://www.readbyqxmd.com/read/29027483/cdk4-6-blockade-in-breast-cancer-current-experience-and-future-perspectives
#11
Dimitrios Zardavas, Noam Pondé, Konstantinos Tryfonidis
Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer...
October 23, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28961554/cdk4-6-inhibition-in-early-and-metastatic-breast-cancer-a-review
#12
REVIEW
A F de Groot, C J Kuijpers, J R Kroep
Breast cancer (BC) is responsible for 14% of cancer-related deaths in women [1]. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy...
November 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28875723/ribociclib-for-post-menopausal-women-with-hr-her2-advanced-or-metastatic-breast-cancer
#13
REVIEW
Mark L Zangardi, Laura M Spring, Gayle C Blouin, Aditya Bardia
The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone. Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib...
November 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28838206/discovery-and-development-of-novel-therapies-in-advanced-breast-cancer-rapid-development-of-ribociclib
#14
C Germa, M Miller, P Mukhopadhyay, B Hewes, G Caponigro, S J Scherer, S Hirawat
No abstract text is available yet for this article.
August 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28804155/insulin-degludec-liraglutide
#15
REVIEW
Danial E Baker
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers...
May 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/28758424/ribociclib-for-the-treatment-of-advanced-hormone-receptor-positive-her2-negative-breast-cancer
#16
Sara López-Tarruella, Yolanda Jerez, Iván Márquez-Rodas, Isabel Echavarria, Miguel Martin
CDK4/6 inhibitors are a promising new class of drugs for hormone-receptor-positive breast cancer and have been shown to overcome and delay hormone resistance in advanced breast cancer. Ribociclib, a selective oral inhibitor of CDK4/6, was approved by the US FDA for first-line treatment of hormone-receptor-positive/HER2-negative metastatic breast cancer. This review summarizes the clinical evidence available for ribociclib, from preclinical data to the pivotal studies, with a special focus on toxicity and its management...
July 31, 2017: Future Oncology
https://www.readbyqxmd.com/read/28741274/cyclin-dependent-kinase-4-6-inhibitors-in-breast-cancer-palbociclib-ribociclib-and-abemaciclib
#17
REVIEW
Dorota Kwapisz
PURPOSE: The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression and its dysregulation is an important contributor to endocrine therapy resistance. CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising results of efficacy and manageable safety profiles. The main objective of this review is to discuss preclinical and clinical data to date, and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in breast cancer...
July 24, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28706010/clinical-management-of-potential-toxicities-and-drug-interactions-related-to-cyclin-dependent-kinase-4-6-inhibitors-in-breast-cancer-practical-considerations-and-recommendations
#18
REVIEW
Laura M Spring, Mark L Zangardi, Beverly Moy, Aditya Bardia
Aberrations of the cell cycle are pervasive in cancer, and selective cell cycle inhibition of cancer cells is a target of choice for a number of novel cancer therapeutics. Cyclin-dependent kinases (CDKs) are key regulatory enzymes that control cell cycle transitions and the commitment to cell division. Palbociclib and ribociclib are both orally active, highly selective reversible inhibitors of CDK4 and CDK6 that are approved by the U.S. Food and Drug Administration (FDA) for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies...
September 2017: Oncologist
https://www.readbyqxmd.com/read/28680952/a-review-of-fulvestrant-in-breast-cancer
#19
REVIEW
Mark R Nathan, Peter Schmid
Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days...
2017: Oncology and Therapy
https://www.readbyqxmd.com/read/28657360/a-current-and-comprehensive-review-of-cyclin-dependent-kinase-inhibitors-for-the-treatment-of-metastatic-breast-cancer
#20
Burak Bilgin, Mehmet A N Sendur, Didem Şener Dede, Muhammed Bülent Akıncı, Bülent Yalçın
BACKGROUND: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. SCOPE: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC)...
September 2017: Current Medical Research and Opinion
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