scholarly journals The Unique Pharmacometrics of Small Molecule Therapeutic Drug Tracer Imaging for Clinical Oncology

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2712
Author(s):  
Mark P. S. Dunphy ◽  
Nagavarakishore Pillarsetty
Keyword(s):  
Small Molecule ◽  
Response Assessment ◽  
Imaging Biomarkers ◽  
Cancer Drug ◽  
Therapeutic Drug ◽  
Therapeutic Drugs ◽  
Tracer Imaging ◽  
Tumor Pharmacokinetics ◽  
Dosing Strategy

Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers.

scholarly journals Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1340 ◽  
Author(s):  
Olaia Martinez-Iglesias ◽  
Alba Casas-Pais ◽  
Raquel Castosa ◽  
Andrea Díaz-Díaz ◽  
Daniel Roca-Lema ◽  
...  
Keyword(s):  
Small Molecule ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
E3 Ubiquitin Ligase ◽  
Therapeutic Drug ◽  
Mesenchymal Transition ◽  
E Cadherin

The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression.

scholarly journals Optical Fibre-Enabled Photoswitching for Localised Activation of an Anti-Cancer Therapeutic Drug

2021 ◽  
Vol 22 (19) ◽  
pp. 10844
Author(s):  
Kathryn A. Palasis ◽  
Noor A. Lokman ◽  
Bryden C. Quirk ◽  
Alaknanda Adwal ◽  
Loretta Scolaro ◽  
...  
Keyword(s):  
Optical Fibre ◽  
Fluorescent Microscopy ◽  
Cancer Drug ◽  
Therapeutic Drug ◽  
Optical Fibres ◽  
Cancer Cell Death ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
Hct 116

Local activation of an anti-cancer drug when and where needed can improve selectivity and reduce undesirable side effects. Photoswitchable drugs can be selectively switched between active and inactive states by illumination with light; however, the clinical development of these drugs has been restricted by the difficulty in delivering light deep into tissue where needed. Optical fibres have great potential for light delivery in vivo, but their use in facilitating photoswitching in anti-cancer compounds has not yet been explored. In this paper, a photoswitchable chemotherapeutic is switched using an optical fibre, and the cytotoxicity of each state is measured against HCT-116 colorectal cancer cells. The performance of optical-fibre-enabled photoswitching is characterised through its dose response. The UV–Vis spectra confirm light delivered by an optical fibre effectively enables photoswitching. The activated drug is shown to be twice as effective as the inactive drug in causing cancer cell death, characterised using an MTT assay and fluorescent microscopy. This is the first study in which a photoswitchable anti-cancer compound is switched using an optical fibre and demonstrates the feasibility of using optical fibres to activate photoswitchable drugs for potential future clinical applications.

Novel Small Molecule Inhibitors of Programmed Cell Death (PD)-1, and its Ligand, PD-L1 in Cancer Immunotherapy: A Review Update of Patent Literature

2019 ◽  
Vol 14 (2) ◽  
pp. 100-112 ◽  
Author(s):  
Spandana R. Kopalli ◽  
Tae-Bong Kang ◽  
Kwang-Ho Lee ◽  
Sushruta Koppula
Keyword(s):  
Cancer Immunotherapy ◽  
Small Molecule ◽  
Critical Role ◽  
Experimental Studies ◽  
World Intellectual Property Organization ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Patent Literature

Background:In the last few decades, cancer immunotherapy has been extensively researched, and novel checkpoint signaling mechanisms involving Programmed Death (PD)-1 and PDLigand 1 (PD-L1) receptors have been targeted. The PD-1/PD-L1 binding and interaction play a critical role in the development of malignancies.Objective:The present review focuses on recent patents on the pharmacological and biological cancerregulating properties of PD-1/PD-L1 inhibitors involved in immunotherapeutic cancer drug development.Methods:Thorough patent literature search published during the last seven years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents, to identify PD-1/PD-L1-targeting small molecule immunomodulators.Results:Several small molecule PD-1/PD-L1 inhibitors were patented for regulation of tumor progression by academic and industry-associated investigators. Most of the claimed patents have been validated and confined to in vitro and in vivo mouse models limiting their entry into clinical settings. Majority of the patents are claimed by the researchers at Aurigene Ltd. (India) on novel peptidomimetic compounds. It is worth to be noted that macrocyclic compounds such as the peptides QP20, HD20, WQ20, SQ20, and CQ-22 from Bristol-Myers Squibb (BMS) Company, biaryl, and heterocyclic derivatives including 1,3-dihydroxy-phenyl compounds were efficient in regulating the PD-1/PD-L1 protein-protein binding and interaction compared to those of the approved monoclonal antibodies.Conclusion:PD-1/PD-L1 inhibitors show significant anti-cancer responses as stand-alone agents and in combination with other cancer therapies. More efficient experimental studies and clinical trials are necessary to evaluate the host-tumor cells’ interactions. Understanding the cancer microenvironment, and identifying specific biomarkers and X-ray crystalline structures of PD-1/PD-L1 complexes, including molecular and genomic signature studies are essential to determine the feasibility of PD-1/PD-L1 inhibitors for development into drug-like cancer immunotherapeutics.

scholarly journals Monitoring the Fate of Orally Administered PLGA Nanoformulation for Local Delivery of Therapeutic Drugs

Pharmaceutics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 658 ◽  
Author(s):  
Lucia Morelli ◽  
Sara Gimondi ◽  
Marta Sevieri ◽  
Lucia Salvioni ◽  
Maria Guizzetti ◽  
...  
Keyword(s):  
Oral Administration ◽  
Systemic Exposure ◽  
Plga Nanoparticles ◽  
In Vivo Studies ◽  
Cancer Drug ◽  
Therapeutic Drugs ◽  
Human Disorders ◽  
Carcinoma Colon

One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract; (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells; (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure; (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders.

NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, prevents breast cancer metastasis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13163-13163 ◽  
Author(s):  
E. Kawahara ◽  
O. Ohmori ◽  
K. Nonomura ◽  
Y. Murakami ◽  
D. Tomioka ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Small Molecule ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Dual Inhibitor ◽  
Normal Cells ◽  
Dose Dependent

13163 Background: Focal Adhesion Kinase (FAK) and Insulin-like Growth Factor-1 Receptor (IGF-IR) kinase are attractive anti-cancer drug targets because they are both drivers of tumor cell proliferation, migration, and survival. Although virtually every cell type expresses FAK, it is generally overexpressed in tumor cells. FAK levels are greatest in highly metastatic tumors. A selective FAK inhibitor would be expected to halt or kill invasive tumor cells, and potentially interfere with normal cell migration (e.g. endothelial cells). IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: NVP-TAE226, a novel small molecule developed as an inhibitor of FAK, was evaluated in kinase enzymatic assays, cell-based kinase assays and 4T1 metastatic breast carcinoma in vivo model. Results: NVP-TAE226 inhibits FAK with low nanomolar IC50 values in a purified kinase enzymatic assay. In cell-based kinase assays, FAK and IGF-IR kinase were inhibited with an IC50 range of 100 to 300 nM compared to the other kinases tested which were >10-fold less sensitive. Oral administration of NVP-TAE226 inhibited 4T1 murine breast tumor growth and metastasis to the lung in a dose-dependent manner. The compound was well tolerated in mice as determined by measuring changes in body weight. The highest dose of 100 mg/kg, qd, 5x/week showed T/C value of 18%. Inhibition of FAK autophosphorylation at Y397 and Akt phosphorylation at Serine473 was observed in a dose-dependent manner in 4T1 breast carcinoma. Conclusions: NVP-TAE226 represents a novel class of selective and small molecule kinase inhibitors that have potential clinical applications with a potent in vivo activity. [Table: see text]

scholarly journals Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)

2021 ◽  
Vol 22 (2) ◽  
pp. 575
Author(s):  
Markus Wild ◽  
Jintawee Kicuntod ◽  
Lisa Seyler ◽  
Christina Wangen ◽  
Luca D. Bertzbach ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Clinical Symptoms ◽  
Drug Combinations ◽  
Murine Cytomegalovirus ◽  
Fixed Dose ◽  
Cancer Drug ◽  
Therapeutic Drug ◽  
Immunocompetent Mice

Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs’ antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs.

120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose Homeostasis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 120-LB
Author(s):  
ABUDUKADIER ABULIZI ◽  
REBECCA L. CARDONE ◽  
STEPHAN SIEBEL ◽  
CHARLES KUNG ◽  
RICHARD KIBBEY
Keyword(s):  
Pyruvate Kinase ◽  
Small Molecule ◽  
Glucose Homeostasis

Quantitative Ranking of Ligand Binding Kinetics with a Multiscale Milestoning Simulation Approach

2018 ◽  
Author(s):  
Benjamin R. Jagger ◽  
Christoper T. Lee ◽  
Rommie Amaro
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Small Molecule ◽  
Brownian Dynamics ◽  
Model Simulation ◽  
Computational Cost ◽  
Lead Selection ◽  
Delta G ◽  
Dynamics Simulations

<p>The ranking of small molecule binders by their kinetic (kon and koff) and thermodynamic (delta G) properties can be a valuable metric for lead selection and optimization in a drug discovery campaign, as these quantities are often indicators of in vivo efficacy. Efficient and accurate predictions of these quantities can aid the in drug discovery effort, acting as a screening step. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon’s, koff’s, and G’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, -cyclodextrin, based on predicted kon’s and koff’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long-timescale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish “best practices” for its future use.</p>

Novel Phytochemical Constituents and their Potential to Manage Diabetes

2020 ◽  
Vol 26 ◽  
Author(s):  
Shaik Ibrahim Khalivulla ◽  
Arifullah Mohammed ◽  
Kokkanti Mallikarjuna
Keyword(s):  
Natural Products ◽  
Large Population ◽  
World Health ◽  
In Vivo Studies ◽  
Antidiabetic Activity ◽  
Therapeutic Drug ◽  
Pharmacological Activities ◽  
Chemical Structures

Background: Diabetes is a chronic disease affecting a large population worldwide and stands as one of the major global health challenges to be tackled. According to World Health Organization, about 400 million are having diabetes worldwide and it is the seventh leading cause of deaths in 2016. Plant based natural products had been in use from ancient time as ethnomedicine for the treatment of several diseases including diabetes. As a result of that, there are several reports on plant based natural products displaying antidiabetic activity. In the current review, such antidiabetic potential compounds reported from all plant sources along with their chemical structures are collected, presented and discussed. This kind of reports are essential to pool the available information to one source followed by statistical analysis and screening to check the efficacy of all known compounds in a comparative sense. This kind of analysis can give rise to few numbers of potential compounds from hundreds, whom can further be screened through in vitro and in vivo studies, and human trails leading to the drug development. Methods: Phytochemicals along with their potential antidiabetic property were classified according to their basic chemical skeleton. The chemical structures of all the compounds with antidiabetic activities were elucidated in the present review. In addition to this, the distribution and their other remarkable pharmacological activities of each species is also included. Results: The scrutiny of literature led to identification of 44 plants with antidiabetic compounds (70) and other pharmacological activities. For the sake of information, the distribution of each species in the world is given. Many plant derivatives may exert antidiabetic properties by improving or mimicking the insulin production or action. Different classes of compounds including sulfur compounds (1-4), alkaloids (5-11), phenolic compounds (12-17), tannins (18-23), phenylpropanoids (24-27), xanthanoids (28-31), amino acid (32), stilbenoid (33), benzofuran (34), coumarin (35), flavonoids (36-49) and terpenoids (50-70) were found to be active potential compounds for antidiabetic activity. Of the 70 listed compounds, majorly 17 compounds are from triterpenoids, 13 flavonoids and 7 are from alkaloids. Among all the 44 plant species, maximum number (7) of compounds are reported from Lagerstroemia speciosa followed by Momordica charantia (6) and S. oblonga with 5 compounds. Conclusion: This is the first paper to summarize the established chemical structures of phytochemicals that have been successfully screened for antidiabetic potential and their mechanisms of inhibition. The reported compounds could be considered as potential lead molecules for the treatment of type-2 diabetes. Further, molecular and clinical trials are required to select and establish the therapeutic drug candidates.

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