scholarly journals Marine-Derived Natural Products as ATP-Competitive mTOR Kinase Inhibitors for Cancer Therapeutics

2021 ◽  
Vol 14 (3) ◽  
pp. 282
Author(s):  
Shraddha Parate ◽  
Vikas Kumar ◽  
Gihwan Lee ◽  
Shailima Rampogu ◽  
Jong Chan Hong ◽  
...  
Keyword(s):  
Natural Products ◽  
In Silico ◽  
Cellular Proliferation ◽  
Kinase Inhibitors ◽  
Binding Free Energy ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapeutics ◽  
Mtor Inhibitors ◽  
Binding Pocket ◽  
Pharmacophore Modeling

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying a quintessential role in cellular proliferation and survival. Aberrations in the mTOR signaling pathway have been reported in numerous cancers including thyroid, lung, gastric and ovarian cancer, thus making it a therapeutic target. To attain this objective, an in silico investigation was designed, employing a pharmacophore modeling approach. A structure-based pharmacophore (SBP) model exploiting the key features of a selective mTOR inhibitor, Torkinib directed at the ATP-binding pocket was generated. A Marine Natural Products (MNP) library was screened using SBP model as a query. The retrieved compounds after consequent drug-likeness filtration were subjected to molecular docking with mTOR, thus revealing four MNPs with better scores than Torkinib. Successive refinement via molecular dynamics simulations demonstrated that the hits formed crucial interactions with key residues of the pocket. Furthermore, the four identified hits exhibited good binding free energy scores through MM-PBSA calculations and the subsequent in silico toxicity assessments displayed three hits deemed essentially non-carcinogenic and non-mutagenic. The hits presented in this investigation could act as potent ATP-competitive mTOR inhibitors, representing a platform for the future discovery of drugs from marine natural origin.

New Frontiers in Mucositis

2012 ◽  
pp. 545-551 ◽  
Author(s):  
Douglas E. Peterson ◽  
Dorothy M. Keefe ◽  
Stephen T. Sonis
Keyword(s):  
Kinase Inhibitors ◽  
Management Strategies ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapeutics ◽  
Mtor Inhibitors ◽  
Mucosal Injury ◽  
Mucosal Damage ◽  
Nucleotide Polymorphisms ◽  
Oncology Patient ◽  
Novel Technologies

Overview: Mucositis is among the most debilitating side effects of radiotherapy, chemotherapy, and targeted anticancer therapy. Research continues to escalate regarding key issues such as etiopathology, incidence and severity across different mucosae, relationships between mucosal and nonmucosal toxicities, and risk factors. This approach is being translated into enhanced management strategies. Recent technology advances provide an important foundation for this continuum. For example, evolution of applied genomics is fostering development of new algorithms to rapidly screen genomewide single-nucleotide polymorphisms (SNPs) for patient-associated risk prediction. This modeling will permit individual tailoring of the most effective, least toxic treatment in the future. The evolution of novel cancer therapeutics is changing the mucositis toxicity profile. These agents can be associated with unique mechanisms of mucosal damage. Additional research is needed to optimally manage toxicity caused by agents such as mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors, without reducing antitumor effect. There has similarly been heightened attention across the health professions regarding clinical practice guidelines for mucositis management in the years following the first published guidelines in 2004. New opportunities exist to more effectively interface this collective guideline portfolio by capitalizing upon novel technologies such as an Internet-based Wiki platform. Substantive progress thus continues across many domains associated with mucosal injury in oncology patients. In addition to enhancing oncology patient care, these advances are being integrated into high-impact educational and scientific venues including the National Cancer Institute Physician Data Query (PDQ) portfolio as well as a new Gordon Research Conference on mucosal health and disease scheduled for June 2013.

Pancreatic endocrine disorders and multiple endocrine neoplasia

2020 ◽  
pp. 2449-2463
Author(s):  
B. Khoo ◽  
T.M. Tan ◽  
S.R. Bloom
Keyword(s):  
Kinase Inhibitors ◽  
Neuroendocrine Tumours ◽  
Mammalian Target Of Rapamycin ◽  
Peptide Receptor Radionuclide Therapy ◽  
Mtor Inhibitors ◽  
Somatostatin Analogues ◽  
Endocrine Disorders ◽  
Pancreatic Neuroendocrine Tumours ◽  
Islet Cell Tumours ◽  
Cancer Syndromes

Pancreatic neuroendocrine tumours (islet-cell tumours) are rare and usually sporadic, but they may be associated with complex familial endocrine cancer syndromes. Recognized types of pancreatic neuroendocrine tumours are those that are non-functioning (often advanced at diagnosis and presenting with mass effects due to the absence of symptoms attributable to hormone hypersecretion), insulinoma (the most frequent type), and others including gastrinoma, VIPoma, and glucagonoma. The following should be considered in addition to the symptomatic treatments: surgical resection—the only curative treatment, but not possible in many cases; tyrosine kinase inhibitors which inhibit specific kinases involved in tumour cell proliferation, growth, and angiogenesis; mammalian Target of Rapamycin (mTOR) inhibitors; peptide-receptor radionuclide therapy (radiolabelled somatostatin analogues).

An in silico protocol for identifying mTOR inhibitors from natural products

2014 ◽  
Vol 18 (4) ◽  
pp. 841-852 ◽  
Author(s):  
Lei Chen ◽  
Ling Wang ◽  
Qiong Gu ◽  
Jun Xu
Keyword(s):  
Natural Products ◽  
In Silico ◽  
Mtor Inhibitors

scholarly journals mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

2020 ◽  
Author(s):  
Shi-Yong Sun
Keyword(s):  
Cancer Therapy ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Targeted Cancer Therapy ◽  
Biological Functions ◽  
New Findings ◽  
Survival Signaling ◽  
Mtor Complex 1

Abstract The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

scholarly journals Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

2020 ◽  
Vol 8 (2) ◽  
pp. 293 ◽  
Author(s):  
Ahmed M. Sayed ◽  
Hani A. Alhadrami ◽  
Seham S. El-Hawary ◽  
Rabab Mohammed ◽  
Hossam M. Hassan ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Pyruvate Kinase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Enzyme Inhibitor ◽  
Dna Gyrase ◽  
Binding Mode

In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.

Safe and Effective Kinase Inhibitors for the Treatment of Gynecological Cancers: In Silico Approach

2021 ◽  
Vol 22 ◽  
Author(s):  
Vaishali M. Patil ◽  
Abhishek Kumar ◽  
Vaishali Anand ◽  
Priya Bansal ◽  
Neeraj Masand
Keyword(s):  
Mortality Rate ◽  
Anticancer Agents ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
Cancer Therapeutics ◽  
Cancer Drugs ◽  
Gynecological Cancers ◽  
Anti Cancer

Aims: To study various types of gynecological cancers and the available therapeutics to investigate safe and effective drugs. Background: Cancer is the most common cause of mortality throughout the world. When the statistics is considered for gynecological cancers, ovarian, cervical and uterine cancers are among the most prevalent types. They have worst prognosis and the highest mortality rate and by the year 2040 significant increase in mortality rate is predicted. Objective: The major limitation with development of anti-cancer therapeutics for the gynecological cancers are safety of the therapeutics for the developing fetus as well as the mother. Various medicinal classes of natural to synthetic therapeutics have been reported including kinase inhibitors as the most promising category of anti-cancer drugs. Method: A dataset of kinase inhibitory clinically approved anticancer agents was derived through literature review. A QSAR based approach i.e. VEGAQSAR has been applied to evaluate the reproductive and developmental toxicity for the selected class of kinase inhibitors. Result: In the present work, the promising category of anticancer kinase inhibitors has been investigated for its toxicity potential with the help of in silico approach. The anti-cancer kinase inhibitors were categorized based on the found non-toxic or toxic properties towards reproductive and developmental toxicity. Conclusion: Early prediction of the available or proposed anti-cancer therapeutics for their contribution towards developmental and reproductive toxicity is an important criterion for their use in pregnancy associated cancers. The investigation of toxicity profile of available anti-cancer kinase therapeutics will be helpful to design and develop novel and safe anti-cancer drugs in the near future. Other: The study outcomes will benefit the current anticancer drug development efforts.

scholarly journals Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Rachna Raman ◽  
Daniel Vaena
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Immune Therapies ◽  
Localized Renal Cell Carcinoma ◽  
Metastatic Rcc

Localized renal cell carcinoma (RCC) is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR) inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer) has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

Design of Novel Rho Kinase Inhibitors Using Energy Based Pharmacophore Modeling, Shape-Based Screening, in Silico Virtual Screening, and Biological Evaluation

2014 ◽  
Vol 54 (10) ◽  
pp. 2876-2886 ◽  
Author(s):  
Ram Kumar Mishra ◽  
Reshma Alokam ◽  
Sarthak Mohan Singhal ◽  
Geethasai Srivathsav ◽  
Dharamarajan Sriram ◽  
...  
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Rho Kinase Inhibitors

Risk of pneumonitis with mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13573-e13573
Author(s):  
Vishal Navnitray Ranpura ◽  
Shenhong Wu
Keyword(s):  
Clinical Trials ◽  
Cancer Patients ◽  
Meta Analysis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapeutics ◽  
Mtor Inhibitors ◽  
High Grade ◽  
Significant Difference ◽  
American Society

e13573 Background: Pneumonitis is associated with the use of mTOR inhibitors, everolimus and temsirolimus, which have been used widely in cancer therapeutics and clinical trials. Currently, the overall risk of pneumonits in patients treated with mTOR inhibitors has not been defined. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of pneumonitis in cancer patients treated with mTOR inhibitors. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2012 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which patients received treatment with everolimus or temsirolimus as a single agent or in combination with other agents. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. Results: A total of 2,303 patients with a variety of tumors from 18 studies (everolimus: 12, temsirolimus: 6) were included for the analysis. The overall incidences of all-grade and high-grade pneumonitis with mTOR inhibitors were 6.5% (95% CI: 3.7-11.1%) and 2.5% (95% CI 1.2-5.4%) respectively. The risk of all-grade pneumonitis did not vary significantly with tumor types (P=0.079), but vary significantly with their combination with other agents (P<0.001). There was no significant difference between everolimus and temsirolimus in the incidence of all-grade (P=0.22) and high-grade (P=0.28) pneumonitis. In comparison with controls, mTOR inhibitors significantly increased the risk of all-grade (RR=5.2, 95% CI: 2.09-12.93, P<0.001) but not high-grade pneumonits (RR=2.63, 95% CI: 0.66-10.40, P=0.41). Conclusions: The risk of pneumonitis is increased in cancer patients receiving mTOR inhibitors without significant difference between everolimus and temsirolimus.

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