scholarly journals Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule–Related Therapeutic Modalities

2019 ◽  
Vol 47 (10) ◽  
pp. 1122-1135 ◽  
Author(s):  
Donglu Zhang ◽  
Cornelis E.C.A. Hop ◽  
Gabriela Patilea-Vrana ◽  
Gautham Gampa ◽  
Herana Kamal Seneviratne ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Therapeutic Modalities ◽  
Concentration Asymmetry

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi170
Author(s):  
Erica Power ◽  
Juhee Oh ◽  
Jonghoon Choi ◽  
William Elmquist ◽  
David Daniels
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Small Molecule Inhibitors ◽  
Efflux Pump ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Efflux Pump Inhibitor ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

Abstract 4176: Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC

2017 ◽  
Author(s):  
Nellie K. Black ◽  
Mari Iida ◽  
Tamara S. Rodems ◽  
Toni M. Brand ◽  
Randall J. Kimple ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Family Members ◽  
Therapeutic Modalities

scholarly journals Nucleic Acid Drugs—Current Status, Issues, and Expectations for Exosomes

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5002
Author(s):  
Yoji Yamada
Keyword(s):  
Nucleic Acid ◽  
Small Molecule ◽  
Viral Infections ◽  
Genetic Disorders ◽  
Clinical Status ◽  
Lipid Nanoparticles ◽  
Current Status ◽  
Nucleic Acid Therapeutics ◽  
Therapeutic Modalities ◽  
Novel Therapeutic

Nucleic acid drugs are being developed as novel therapeutic modalities. They have great potential to treat human diseases such as cancers, viral infections, and genetic disorders due to unique characteristics that make it possible to approach undruggable targets using classical small molecule or protein/antibody-based biologics. In this review, I describe the advantages, classification, and clinical status of nucleic acid therapeutics. To date, more than 10 products have been launched, and many products have been tested in clinics. To promote the use of nucleic acid therapeutics such as antibodies, several hurdles need to be surmounted. The most important issue is the delivery of nucleic acids and several other challenges have been reported. Recent advanced delivery platforms are lipid nanoparticles and ligand conjugation approaches. With the progress of exosome biology, exosomes are expected to contribute to the solution of various problems associated with nucleic acid drugs.

scholarly journals Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1855 ◽  
Author(s):  
Rongjun He ◽  
Brian Finan ◽  
John P. Mayer ◽  
Richard D. DiMarchi
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Molecular Diversity ◽  
Molecular Mechanisms ◽  
Design Synthesis ◽  
Therapeutic Modalities ◽  
Small Molecule Drugs ◽  
Therapeutic Outcomes ◽  
Oncologic Diseases ◽  
Dose Dependent

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.

scholarly journals Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

2020 ◽  
Vol 117 (29) ◽  
pp. 17195-17203
Author(s):  
Uddhav K. Shigdel ◽  
Seung-Joo Lee ◽  
Mathew E. Sowa ◽  
Brian R. Bowman ◽  
Keith Robison ◽  
...  
Keyword(s):  
Small Molecule ◽  
Structural Changes ◽  
Coiled Coil ◽  
Ternary Complexes ◽  
Surface Topology ◽  
Structural Motif ◽  
Therapeutic Modality ◽  
Target Range ◽  
Therapeutic Modalities ◽  
Fk506 Binding Protein

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein–WDB002 and protein–protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise “undruggable” targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

A privileged ternary blend enabling non-fullerene organic photovoltaics with over 14% efficiency

2020 ◽  
Vol 8 (43) ◽  
pp. 15135-15141
Author(s):  
Jing Yan ◽  
Yuan-Qiu-Qiang Yi ◽  
Jianqi Zhang ◽  
Huanran Feng ◽  
Yanfeng Ma ◽  
...  
Keyword(s):  
Small Molecule ◽  
Organic Photovoltaics ◽  
Power Conversion ◽  
Ternary Blend ◽  
Conversion Efficiencies

Two non-fullerene small molecule acceptors, NT-4F and NT-4Cl, were designed and synthesized. Power conversion efficiencies of 11.44% and 14.55% were achieved for NT-4Cl-based binary and ternary devices, respectively.

The small-molecule antibiotics pipeline: 2014–2018

2019 ◽  
Vol 18 (10) ◽  
pp. 739-739 ◽  
Author(s):  
Cara Lepore ◽  
Lynn Silver ◽  
Ursula Theuretzbacher ◽  
Joe Thomas ◽  
David Visi
Keyword(s):  
Small Molecule
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