Finding melanoma drugs through a probabilistic knowledge graph

10.7287/peerj.preprints.2007v1 ◽

2016 ◽

Author(s):

James P McCusker ◽

Michel Dumontier ◽

Rui Yan ◽

Sylvia He ◽

Jonathan S Dordick ◽

...

Keyword(s):

Systems Biology ◽

Probabilistic Methods ◽

Drug Candidate ◽

Knowledge Graph ◽

Web Interface ◽

Drug Candidates ◽

Probabilistic Knowledge ◽

Data Explosion

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates, however filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein, and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an API or web interface, and has generated 25 high quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

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Finding melanoma drugs through a probabilistic knowledge graph

10.7287/peerj.preprints.2007 ◽

2016 ◽

Cited By ~ 2

Author(s):

James P McCusker ◽

Michel Dumontier ◽

Rui Yan ◽

Sylvia He ◽

Jonathan S Dordick ◽

...

Keyword(s):

Systems Biology ◽

Probabilistic Methods ◽

Drug Candidate ◽

Knowledge Graph ◽

Web Interface ◽

Drug Candidates ◽

Probabilistic Knowledge ◽

Data Explosion

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates, however filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein, and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an API or web interface, and has generated 25 high quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

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Finding melanoma drugs through a probabilistic knowledge graph

10.7287/peerj.preprints.2007v2 ◽

2016 ◽

Author(s):

James P McCusker ◽

Michel Dumontier ◽

Rui Yan ◽

Sylvia He ◽

Jonathan S Dordick ◽

...

Keyword(s):

Systems Biology ◽

Probabilistic Methods ◽

Drug Candidate ◽

Knowledge Graph ◽

Web Interface ◽

Drug Candidates ◽

Probabilistic Knowledge ◽

Data Explosion

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates, however filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein, and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an API or web interface, and has generated 25 high quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

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Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.721338 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mridu Malik ◽

Yang Yang ◽

Parinaz Fathi ◽

Gretchen J. Mahler ◽

Mandy B. Esch

Keyword(s):

Animal Models ◽

Drug Toxicity ◽

New Drugs ◽

Drug Candidate ◽

Preclinical Studies ◽

Toxicity Screening ◽

Drug Candidates ◽

Microphysiological Systems

Identification and approval of new drugs for use in patients requires extensive preclinical studies and clinical trials. Preclinical studies rely on in vitro experiments and animal models of human diseases. The transferability of drug toxicity and efficacy estimates to humans from animal models is being called into question. Subsequent clinical studies often reveal lower than expected efficacy and higher drug toxicity in humans than that seen in animal models. Microphysiological systems (MPS), sometimes called organ or human-on-chip models, present a potential alternative to animal-based models used for drug toxicity screening. This review discusses multi-organ MPS that can be used to model diseases and test the efficacy and safety of drug candidates. The translation of an in vivo environment to an in vitro system requires physiologically relevant organ scaling, vascular dimensions, and appropriate flow rates. Even small changes in those parameters can alter the outcome of experiments conducted with MPS. With many MPS devices being developed, we have outlined some established standards for designing MPS devices and described techniques to validate the devices. A physiologically realistic mimic of the human body can help determine the dose response and toxicity effects of a new drug candidate with higher predictive power.

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A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern

10.1101/2021.08.08.455562 ◽

2021 ◽

Author(s):

Teresa R. Wagner ◽

Daniel Schnepf ◽

Julius Beer ◽

Karin Klingel ◽

Natalia Ruetalo ◽

...

Keyword(s):

Lethal Dose ◽

Survival Rates ◽

Drug Candidate ◽

Lethal Challenge ◽

Drug Candidates ◽

High Affinity ◽

Neutralizing Capacity ◽

Future Drug

The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.

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A Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies

10.26434/chemrxiv.9582527.v1 ◽

2019 ◽

Cited By ~ 3

Author(s):

Anna Notaro ◽

Angelo Frei ◽

Riccardo Rubbiani ◽

Marta Jakubaszek ◽

Uttara Basu ◽

...

Keyword(s):

Chemotherapeutic Agent ◽

Biological Properties ◽

In Vivo Studies ◽

Drug Candidate ◽

Paramagnetic Resonance ◽

In Vivo Models ◽

Drug Candidates ◽

X Ray Crystallography

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a surge for new chemotherapeutic drugs. More specifically, the discovery of new drug candidates able to overcome severe side effects, the occurrence of resistance and the inefficacy toward metastatic tumours is highly desirable. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely [Ru(DIP)2(sq)]PF6 (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated to the catecholate moiety. Several pieces of experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrate that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinised in vitro and in vivo, and the results highlight the tremendous potential of this complex as a chemotherapeutic agent against cancer. Ru-sq was notably found have a much higher cytotoxic activity than cisplatin on several cell lines (i.e. in the nanomolar range), and, contrary to cisplatin, to have mitochondrial disfunction as one of its modes of action. The multicellular targets of Ru-sq could potentially be the key to overcome one of the main drawbacks of cisplatin i.e. the occurrence of resistance. Moreover, Ru-sq exhibited impressing activity on Multi Cellular Tumour Spheroids (MCTS) model, leading to a growth inhibition of the tumour even 13 days after treatment (20 μM). Very importantly, using two different in vivo models, it could be demonstrated that this compound is extremely well-tolerated by mice and has a very promising activity, curing, in some cases, tumour-bearing mice.<br>

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Cryptotanshinone Inhibits the Growth of HCT116 Colorectal Cancer Cells Through Endoplasmic Reticulum Stress-Mediated Autophagy

Frontiers in Pharmacology ◽

10.3389/fphar.2021.653232 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaojing Fu ◽

Wenwen Zhao ◽

Kangkang Li ◽

Jingyi Zhou ◽

Xuehong Chen

Keyword(s):

Colorectal Cancer ◽

Er Stress ◽

Salvia Miltiorrhiza ◽

Underlying Mechanism ◽

Drug Candidate ◽

Drug Candidates ◽

Colorectal Cancer Cells ◽

Sw620 Cells

Among cancers, colorectal cancer (CRC) has one of the highest annual incidence and death rates. Considering severe adverse reactions associated with classical chemotherapy medications, traditional Chinese medicines have become potential drug candidates. In the current study, the effects of cryptotanshinone (CPT), a major component of Salvia miltiorrhiza Bunge (Danshen) on CRC and underlying mechanism were explored. First of all, data from in vitro experiments and in vivo zebrafish models indicated that CPT selectively inhibited the growth and proliferation of HCT116 and SW620 cells while had little effect on SW480 cells. Secondly, both ER stress and autophagy were associated with CRC viability regulation. Interestingly, ER stress inhibitor and autophagy inhibitor merely alleviated cytotoxic effects on HCT116 cells in response to CPT stimulation, while have little effect on SW620 cells. The significance of apoptosis, autophagy and ER stress were verified by clinical data from CRC patients. In summary, the current study has revealed the anti-cancer effects of CPT in CRC by activating autophagy signaling mediated by ER stress. CPT is a promising drug candidate for CRC treatment.

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A Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies

10.26434/chemrxiv.9582527 ◽

2019 ◽

Author(s):

Anna Notaro ◽

Angelo Frei ◽

Riccardo Rubbiani ◽

Marta Jakubaszek ◽

Uttara Basu ◽

...

Keyword(s):

Chemotherapeutic Agent ◽

Biological Properties ◽

In Vivo Studies ◽

Drug Candidate ◽

Paramagnetic Resonance ◽

In Vivo Models ◽

Drug Candidates ◽

X Ray Crystallography

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a surge for new chemotherapeutic drugs. More specifically, the discovery of new drug candidates able to overcome severe side effects, the occurrence of resistance and the inefficacy toward metastatic tumours is highly desirable. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely [Ru(DIP)2(sq)]PF6 (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated to the catecholate moiety. Several pieces of experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrate that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinised in vitro and in vivo, and the results highlight the tremendous potential of this complex as a chemotherapeutic agent against cancer. Ru-sq was notably found have a much higher cytotoxic activity than cisplatin on several cell lines (i.e. in the nanomolar range), and, contrary to cisplatin, to have mitochondrial disfunction as one of its modes of action. The multicellular targets of Ru-sq could potentially be the key to overcome one of the main drawbacks of cisplatin i.e. the occurrence of resistance. Moreover, Ru-sq exhibited impressing activity on Multi Cellular Tumour Spheroids (MCTS) model, leading to a growth inhibition of the tumour even 13 days after treatment (20 μM). Very importantly, using two different in vivo models, it could be demonstrated that this compound is extremely well-tolerated by mice and has a very promising activity, curing, in some cases, tumour-bearing mice.<br>

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Systems biology–based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma

Science Translational Medicine ◽

10.1126/scitranslmed.aat0150 ◽

2018 ◽

Vol 10 (464) ◽

pp. eaat0150 ◽

Cited By ~ 26

Author(s):

Lei Huang ◽

Sarah Garrett Injac ◽

Kemi Cui ◽

Frank Braun ◽

Qi Lin ◽

...

Keyword(s):

Systems Biology ◽

Cardiac Glycoside ◽

Simulated Annealing Algorithm ◽

Drug Repositioning ◽

Plasma Concentrations ◽

Drug Candidates ◽

Growth Of Groups ◽

New Treatments

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for “rational” targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates. From more than 1300 drug candidates studied, we identified five members of the cardiac glycoside family as potentially inhibiting the growth of groups 3 and 4 MB and subsequently confirmed this in vitro. Systemic in vivo treatment of orthotopic patient-derived xenograft (PDX) models of groups 3 and 4 MB with digoxin, a member of the cardiac glycoside family approved for the treatment of heart failure, prolonged animal survival at plasma concentrations known to be tolerated in humans. These results demonstrate the power of a systematic drug repositioning method in identifying a potential treatment for MB. Our strategy could potentially be used to accelerate the repositioning of treatments for other human cancers that lack clearly defined rational targets.

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Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

Current Medicinal Chemistry ◽

10.2174/0929867325666181001115225 ◽

2019 ◽

Vol 26 (25) ◽

pp. 4799-4831 ◽

Cited By ~ 4

Author(s):

Jiahua Cui ◽

Xiaoyang Liu ◽

Larry M.C. Chow

Keyword(s):

Molecular Mechanisms ◽

Metastatic Cancer ◽

Drug Candidates ◽

Chemical Structures ◽

Transporter Family ◽

Promising Area ◽

New Generation ◽

Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

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