Computational evaluation of some compounds as potential anti-breast cancer agents

Background The emergence of high resistance and toxicity of the existing anti-breast cancer drugs have demanded the need to design new drugs with improved activities against breast cancer. A computational technique incorporating quantitative structure–activity relationship and virtual template-based design was carried out to evaluate thirty-four compounds from derivatives of thiophene, pyrimidine, coumarin, pyrazole and pyridine with anti-breast cancer activities. The chemical structures of the compounds were drawn with chem draw v.12.0.2 and they were optimized using Spartan 14 software. The molecular descriptors were calculated with the aid of PaDel descriptor software. The dataset was curated and then divided into training and test set that was used to generate and validate the model. Results The first out of the four models generated was chosen as the paramount model with statistical validations of R2 = 0.9847, $$R_{{{\text{adj}}}}^{2}$$ R adj 2 = 0.9814, $$Q_{{{\text{cv}}}}^{2}$$ Q cv 2 = 0.9763, min expt. error for non-significant LOF (95%) = 0.0679, an external validation $$R_{{{\text{test}}}}^{2}$$ R test 2 of 0.8240 and coefficient of Y-randomization ($${\text{cR}}_{{\text{p}}}^{2}$$ cR p 2 ) = 0.8200, which confirm the robustness of the model. Conclusions The high predictive power of the generated model describes the models’ reliability and the designed compounds pointed out compound 2 with pGI50 = 4.2504 as the best designed compound to inhibit breast cancer, compared to its co-designed compounds and the template. The results of this research provide vital information to the pharmaceutical chemists and the pharmacologist in the course of developing new breast cancer drugs.

Overall survival, quality of life and magnitude of clinical benefit of breast cancer drugs over the last 25 years.

6571 Background: The American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-VF), and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) are validated tools quantifying the clinical benefit for cancer drugs. Here, we assess the overall survival (OS), quality of life (QoL) and magnitude of clinical benefit of trials supporting breast cancer drug approval by the US Food and Drug Administration (FDA) in the last 25 years. Methods: We searched Drugs@FDA website for all breast cancer drug approvals from January 1, 1995 to December 30, 2020. Drug labels and reports of registration trials were reviewed. We collected data on trial characteristics, efficacy, toxicity and QoL. When more than one study supported a single indication, we preferred efficacy-oriented endpoints (typically OS) to QoL. We excluded trials supporting accelerated-approval indications if these were converted to regular approval during the study period. We scored clinical benefit using the ASCO-CRC in palliative setting, and ASCO-VF and ESMO-MCBS in both curative and palliative setting. Substantial clinical benefit was defined as: OS gains ≥2.5 months and progression-free survival gains ≥ 3 months for ASCO-CRC criteria; ASCO-VF scores ≥ 45 and grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Trends over time were assessed using Chi-squared test for trend. Results: We identified 51 trials supporting the approval of 32 individual drugs for 51 indications; 12 (24%) were in the curative setting and 39 (76%) in the palliative setting. At the time of approval, 8 (16%) trials reported significant improvement in OS. QoL was reported in 22 trials (43%). Among these, 8 (36%) showed improvement in QoL. For curative intent, we applied ASCO-VF and ESMO-MCBS score to 11 (92%) trials, finding clinical benefit in 10 (91%) and 2 (18%) trials, respectively. In the palliative setting, we used ASCO-CRC, ASCO-VF and ESMO-MCBS scores to rate 32 (82%), 33 (85%) and 38 (97%) trials. Substantial clinical benefit was observed in 20 (63%), 12 (36%) and 7 (19%) trials, respectively. Over time, there has been a decrease in the number of trials supporting approval based on OS (1996-2003 50% vs 2004-12 38% vs 2013-20 13%, P trend = 0.033). There were no statistically significant changes over time in QoL, ASCO-CRC, ASCO-VF and ESMO-MCBS scores. Conclusions: For palliative intent, most trials supporting FDA approval of breast cancer drugs do not meet the ASCO-VF or ESMO-MCBS criteria for substantial clinical benefit. There is substantial inter-framework variability in the assessment of clinical benefit in the curative setting. Over time, there has been a substantial shift towards use of surrogate endpoints as the basis for approval without a clear improvement in substantial clinical benefit.

Patient-reported outcomes in breast cancer FDA drug labels and review documents

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.

Computational Bioactivity Analysis and Bioisosteric Investigation of the Approved Breast Cancer Drugs Proposed New Design Drug Compounds: Increased Bioactivity Coming with Silicon and Boron

Background: The breast cancer takes the first place among women cancer diagnosed worldwide. Objective: Based on the preferential multi-targeted approach on cancer therapy, we, in this study, aimed to design in silico drug candidates possessing multi-targeted bioactivity to cope with multi-drug resistance using the known drug structures, molecular modeling, and ADME parameters. Methods: We first evaluated the bioactivity score of the approved breast cancer drugs across the top-three drug targets GPCR, kinase, and nuclear receptors and calculated their physico-chemical properties to see their drug-likeness profiles. Among 29 approved drugs, Aromasin and Capecitabine showed the broadest bioactivity across the targets listed. By using molecular modeling and bioisosteric modifications, and applying two filtering approaches, we investigated thirty-one analogues of Aromasin and Capecitabine. Results : Software prediction resulted in that the compounds A14, C4, and C13 replaced with B(OH)2 and/or Si(CH3)3 showed a broader spectrum of biological activity with a multi-targeted manner than even the approved analogs. Conclusion: The interesting point of these new design molecules is to have either silicon and/or boron incorporation. The increased bioactivity effect of Silicon and Boron incorporation is also seen in the recent approved drug list of FDA and in clinical trials ongoing. Our new design boron and silicon based molecules appeared to be promising candidates for breast cancer treatment to be tested in vitro, in vivo, and in clinic for further pharmacological investigations.

Hibiscus Anthocyanins Can Selectively Modulate Estrogen Receptor Activity with Favorable Toxicology: a Computational Analysis

The estrogen hormone receptor (ER) mediated gene expression mainly regulate the development and physiology of primary and secondary reproductive system alongside bone-forming, metabolism and behaviour. Over-expressed ER is associated with several pathological conditions and play a key role in breast cancer occurrence, progression and metastasis. Hibiscus sabdariffa L. or roselle is a rich source of naturally occurring polyphenolic compounds including anthocyanins and reportedly have strong estrogenic activity. To validate these findings, we have investigated the estrogen receptor binding affinity and safety of some previously recorded polyphenols using a suite of computational methods. Our investigation showed the estrogen-receptor binding potential of Pelargonidin, Delphinidin, Cyanidin, and Hibiscetin are more efficient than popular breast cancer drugs, Tamoxifen and Raloxifene, with favourable toxicological parameters and low half maximal inhibitory concentration. This is the first report to investigate the phytochemical basis of estrogenic activity of Hibiscus sabdariffa L.