Abstract 24: HMBD001, a novel anti-ErbB3 antibody with a unique mechanism of action, effectively inhibits tumor growth in pre-clinical models of ErbB3+ solid tumors

2017 ◽  
Author(s):  
Jerome D. Boyd-Kirkup ◽  
Dipti Thakkar ◽  
Piers J. Ingram
Keyword(s):  
Tumor Growth ◽  
Solid Tumors ◽  
Mechanism Of Action ◽  
Clinical Models ◽  
Unique Mechanism

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Select Signaling Proteins Following Sub-Chronic Administration in the Rat

2020 ◽  
Vol 13 ◽  
Author(s):  
Ritesh Daya ◽  
Joella Ho ◽  
Sharon Thomson ◽  
Jayant Bhandari ◽  
Ram K. Mishra
Keyword(s):  
Frontal Cortex ◽  
Mechanism Of Action ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D2 Receptors ◽  
Dopamine D2 ◽  
Therapeutic Mechanism ◽  
Clinical Models ◽  
G Protein Coupled

Background: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)- pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of Prolyl-Leucyl-Glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. Objective: in this study, we sought to examine the biomolecular underpinnings of PAOPA‘s therapeutic outcomes in preclinical models of schizophrenia. Method: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin-3), and phosphorylated mitogenactivated protein kinase (MAPKs), namely, extracellular signal-regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. Results: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore PAOPA’s therapeutic mechanism of action for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggestive of a role for PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. Conclusion: While further studies are required to elucidate PAOPA’s mechanism of action, this study builds on prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

scholarly journals Cannabidiol as a potential treatment for psychosis

2019 ◽  
Vol 9 ◽  
pp. 204512531988191 ◽  
Author(s):  
Cathy Davies ◽  
Sagnik Bhattacharyya
Keyword(s):  
Mechanism Of Action ◽  
Psychotic Disorders ◽  
Dopamine D2 Receptor ◽  
Significant Proportion ◽  
D2 Receptor ◽  
Current Evidence ◽  
Novel Treatment ◽  
D2 Antagonist ◽  
Unique Mechanism ◽  
Preclinical Work

Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions that contribute substantially to the global burden of disease. The introduction of dopamine D2 receptor antagonists in the 1950s revolutionised the treatment of psychotic disorders and they remain the mainstay of our treatment arsenal for psychosis. However, traditional antipsychotics are associated with a number of side effects and a significant proportion of patients do not achieve an adequate remission of symptoms. There is therefore a need for novel interventions, particularly those with a non-D2 antagonist mechanism of action. Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action. In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders. We first review the evidence from the perspective of preclinical work and human experimental and neuroimaging studies. We then synthesise the current evidence regarding the clinical efficacy of CBD in terms of positive, negative and cognitive symptoms, safety and tolerability, and potential mechanisms by which CBD may have antipsychotic effects.

Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action

2001 ◽  
Vol 37 (1) ◽  
pp. 97-105 ◽  
Author(s):  
E Erba ◽  
D Bergamaschi ◽  
L Bassano ◽  
G Damia ◽  
S Ronzoni ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Marine Compound ◽  
Ecteinascidin 743 ◽  
Unique Mechanism

scholarly journals Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site

2018 ◽  
Vol 25 (11) ◽  
pp. 1327-1336.e4 ◽  
Author(s):  
Zhenhao Fang ◽  
Christopher B. Marshall ◽  
Tadateru Nishikawa ◽  
Alvar D. Gossert ◽  
Johanna M. Jansen ◽  
...  
Keyword(s):  
Binding Site ◽  
Mechanism Of Action ◽  
Effector Binding ◽  
Unique Mechanism

Efficacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer Medicines

2018 ◽  
Vol 36 (18) ◽  
pp. 1805-1812 ◽  
Author(s):  
Thomas J. Hwang ◽  
Jessica M. Franklin ◽  
Christopher T. Chen ◽  
Julie C. Lauffenburger ◽  
Bishal Gyawali ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Drug Administration ◽  
Mechanism Of Action ◽  
Food And Drug Administration ◽  
Progression Free Survival ◽  
Cancer Drugs ◽  
Serious Adverse Events ◽  
Hazard Ratios ◽  
Fda Approval

Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non–breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non–breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non–breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non–breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy–designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non–breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non–breakthrough-designated drugs.

Abstract B252: The unique mechanism of action of VAL-083 may provide a new treatment option for some chemo-resistant cancers.

2013 ◽  
Author(s):  
Anne Steino ◽  
Jeffrey A. Bacha ◽  
William J. Garner ◽  
Sarath Kanekal ◽  
Zahid H. Siddik ◽  
...  
Keyword(s):  
Treatment Option ◽  
Mechanism Of Action ◽  
New Treatment ◽  
Unique Mechanism

scholarly journals Metformin’s Modulatory Effects on miRNAs Function in Cancer Stem Cells—A Systematic Review

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1401
Author(s):  
Bartosz Malinowski ◽  
Nikola Musiała ◽  
Michał Wiciński
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Solid Tumors ◽  
Cancer Progression ◽  
Mechanism Of Action ◽  
Eligibility Criteria ◽  
Major Function ◽  
Mirnas Expression ◽  
Meta Analyses

Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin’s ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs’ major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.

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