scholarly journals Palbociclib and Ribociclib Analogs Targeting CDK4 and CDK6 for Breast Cancer Treatment: A Molecular Modeling Study

Author(s):  
Dhoha TRIKI ◽  
sravya Kuchibhotla ◽  
Denis Fourches

<div>Palbociclib and Ribociclib are FDA approved drugs that target cyclin dependent kinases CDK4 and CDK6 to treat breast cancer. Herein, we conducted a cheminformatics analysis of a large set of their analogs. The study highlights (i) several clusters of similar compounds with excellent inhibitory profiles, (ii) their shared CDK-ligand intermolecular interactions as predicted by 3D docking, and (iii) key dynamic interactions shared by highly active CDK4/6 inhibitors.<br></div>

2020 ◽  
Author(s):  
Dhoha TRIKI ◽  
sravya Kuchibhotla ◽  
Denis Fourches

<div>Palbociclib and Ribociclib are FDA approved drugs that target cyclin dependent kinases CDK4 and CDK6 to treat breast cancer. Herein, we conducted a cheminformatics analysis of a large set of their analogs. The study highlights (i) several clusters of similar compounds with excellent inhibitory profiles, (ii) their shared CDK-ligand intermolecular interactions as predicted by 3D docking, and (iii) key dynamic interactions shared by highly active CDK4/6 inhibitors.<br></div>


2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Kyungwan Hong ◽  
Kayleigh R. Majercak ◽  
Ester Villalonga-Olives ◽  
Eleanor M. Perfetto

Abstract Background Patient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions. Methods We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted. Results Of 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods. Conclusions Despite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.


Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1488
Author(s):  
Alessandra Ammazzalorso ◽  
Mariangela Agamennone ◽  
Barbara De Filippis ◽  
Marialuigia Fantacuzzi

The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings. The developments of the last five years in the search for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity against different kinases and antiproliferative activity.


2013 ◽  
Author(s):  
Poornima Bhat-Nakshatri ◽  
Chirayu Goswami ◽  
Sunil Badve ◽  
George W. Sledge ◽  
Harikrishna Nakshatri

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Ghazale Fahimian ◽  
Javad Zahiri ◽  
Seyed Shahriar Arab ◽  
Reza H. Sajedi

Abstract Background It often takes more than 10 years and costs more than 1 billion dollars to develop a new drug for a particular disease and bring it to the market. Drug repositioning can significantly reduce costs and time in drug development. Recently, computational drug repositioning attracted a considerable amount of attention among researchers, and a plethora of computational drug repositioning methods have been proposed. This methodology has widely been used in order to address various medical challenges, including cancer treatment. The most common cancers are lung and breast cancers. Thus, suggesting FDA-approved drugs via drug repositioning for breast cancer would help us to circumvent the approval process and subsequently save money as well as time. Methods In this study, we propose a novel network-based method, named RepCOOL, for drug repositioning. RepCOOL integrates various heterogeneous biological networks to suggest new drug candidates for a given disease. Results The proposed method showed a promising performance on benchmark datasets via rigorous cross-validation. The final drug repositioning model has been built based on a random forest classifier after examining various machine learning algorithms. Finally, in a case study, four FDA approved drugs were suggested for breast cancer stage II. Conclusion Results show the potency of the proposed method in detecting true drug-disease relationships. RepCOOL suggested four new drugs for breast cancer stage II namely Doxorubicin, Paclitaxel, Trastuzumab, and Tamoxifen.


2020 ◽  
Author(s):  
◽  
Shanshan Deng ◽  

Triple negative breast cancer (TNBC) has aggressive clinical features strongly associated with poorer overall prognosis and higher mortality rates relative to other molecular subtypes. FDA-approved drugs, such as paclitaxel, are effective in treating TNBC. Yet, treatment failure is commonly observed due to the development of acquired chemoresistance, which remains a clinical challenge for TNBC therapy.


2013 ◽  
Vol 3 (1) ◽  
Author(s):  
Poornima Bhat-Nakshatri ◽  
Chirayu P. Goswami ◽  
Sunil Badve ◽  
George W. Sledge ◽  
Harikrishna Nakshatri

2021 ◽  
Vol 18 (5) ◽  
pp. 6328-6385
Author(s):  
Ana Costa ◽  
◽  
Nuno Vale ◽  

<abstract> <p>Breast cancer is one of the most common cancers and generally affects women. It is a heterogeneous disease that presents different entities, different biological characteristics, and differentiated clinical behaviors. With this in mind, this literature review had as its main objective to analyze the path taken from the simple use of classical drugs to the application of mathematical models, which through the many ongoing studies, have been considered as one of the reliable strategies, explaining the reasons why chemotherapy is not always successful. Besides, the most commonly mentioned strategies are immunotherapy, which includes techniques and therapies such as the use of antibodies, cytokines, antitumor vaccines, oncolytic and genomic viruses, among others, and nanoparticles, including metallic, magnetic, polymeric, liposome, dendrimer, micelle, and others, as well as drug reuse, which is a process by which new therapeutic indications are found for existing and approved drugs. The most commonly used pharmacological categories are cardiac, antiparasitic, anthelmintic, antiviral, antibiotic, and others. For the efficient development of reused drugs, there must be a process of exchange of purposes, methods, and information already available, and for their better understanding, computational mathematical models are then used, of which the methods of blind search or screening, based on the target, knowledge, signature, pathway or network and the mechanism to which it is directed, stand out. To conclude it should be noted that these different strategies can be applied alone or in combination with each other always to improve breast cancer treatment.</p> </abstract>


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