News & Analysis Highlighting the latest news and research in medicinal chemistry
Future
Medicinal Chemistry
Electrically controlled drug-delivery system may help minimize side effects Remotely controlled drug-delivery device may be a step towards ‘smart’ closed-loop drug-eluting systems
Researchers from the University of Pittsburgh (PA, USA) have developed an electrically controlled drug-delivery nanocomposite that is able to release the drug on-demand in response to voltage stimulation. The nanocomposite comprises graphene oxide (GO) deposited inside a conducting polymer scaffold, which was found to exhibit favorable electrical properties. The team loaded the drug-delivery system with anti-inflammatory molecule, dexamethasone. When voltage stimulation was applied, the nanocomposite was found to Eventually, we wish to build release the drug with a linear release profile a close-loop system, which detects a condition and releases at a dosage that could be adjusted by varying the magnitude of stimulation. In the treatment accordingly. absence of stimulation, it was observed that the drug did not passively diffuse from the composite. The group, which was led by Xinyan Tracy Cui, Associate Professor at the University of Pittsburgh, reported that they were able to tailor the properties of the delivery system by decreasing the size and thickness of the GO nanosheets, which in turn influenced drug loading and release profiles. In addition, in vitro cell culture experiments demonstrated that the released drug retained its bioactivity and that no toxic byproducts were leached from the film during electrical stimulation. According to the team, previous versions of the drug-release system were severely
“
”
part of
10.4155/FMC.14.33 © 2014 Future Science Ltd
limited by a finite drug-loading capacity. However, with the addition of the GO nanosheets to the nanocomposite material it was found that the amount of drug that could be released from the system significantly improved, thereby widening the therapeutic range of the device and potentially increasing its lifespan. Commenting on the significance of the results, Cui explained that, conventionally, drugs are delivered systemically (for example orally or intravenously), at a dose that is much higher than that which is required to have a therapeutic effect at the target tissue, often resulting in adverse side effects. Cui commented, “With our on-demand delivery system, these side effects may be avoided because we will be able to release the drug selectively into the target tissue, with a high level of control over the timing of delivery and the magnitude of the dose.” Speaking to Future Medicinal Chemistry, Cui commented that, in terms of future work the team intends to, “continue investigating the ability of the GO nanosheets to finely modulate the dosing range of the drug-delivery system.” The team also plans to study the sensing capability of the composite to detect various biomarkers or neural signals. “Eventually, we wish to build a close-loop system, which detects a condition and releases treatment accordingly,” said Cui.
– Written by Hannah Coaker Source: Weaver CL, Larosa JM, Luo X, Cui XT. Electrically controlled drug delivery from graphene oxide nanocomposite films. ACS Nano. 8 (2), 1834–1843 (2014).
Future Med. Chem. (2014) 6(6), 601–603
ISSN 1756-8919
601
News and Analysis News
New compound could be an ideal candidate for visual restoration in patients with degenerative retinal disorders Millions of people suffer from progressive degeneration of their rods and cones, specialized photoreceptor cells in the outer retina that convert light into visual signals, transmitted to the brain via retinal ganglion cells (RGCs). This degeneration can lead to blindness; however, RGCs typically remain functional even after death of the rods and cones.
“
...favorable spectral sensitivity and selective targeting make DENAQ a prime candidate for visual restoration in patients in degenerative retinal diseases.
”
Now, a team of scientists from the University of California, Berkeley (CA, USA) have reported the temporary restoration of visual function to blind mice, following the intraocular injection of a small molecule, DENAQ. Led by Richard Kramer, professor of neurobiology at the university, the group had previously demonstrated that DENAQ, a photoswitch chemical that changes its conformation in response to light, could confer light sensitivity on certain voltage
gated ion channels. In this latest paper, the researchers tested the action of the small-molecule compound on 3–6 month-old mice carrying a mutation that causes their rods and cones to degenerate within 1 month. By recording neuronal activity from the RGCs using an electrode array, their findings showed that RGCs from the diseased mice conferred strong light sensitivity following treatment with DENAQ. The work studied the effects of the compound on functional, non-functional and degenerated rods and cones, demonstrating that DENAQ only acts on RGCs if the rods and cones have already died. This suggests that degeneration in the outer retina leads to electrophysiological changes in the inner retina, thus allowing DENAQ photosensitization. However, the presence of intact photoreceptors prevents the action of the compound. This selective action may reduce side effects on healthy retina, and, while further studies are required before human trials for the compound, the favorable spectral sensitivity and selective targeting make DENAQ a prime candidate for visual restoration in patients in degenerative retinal diseases.
– Written by James Potticary Source: Tochitsky I, Polosukhina A, Degtyar VE et al. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron doi:10.1016/j.neuron.2014.01.003 (2014) (Epub ahead of print).
Drug repurposing identifies therapeutic agents for gastrointestinal stromal tumors A team of researchers from the University of Pittsburgh Cancer Institute (PA, USA) have discovered potential new uses for two US FDA-approved anticancer drugs for the treatment of gastrointestinal stromal tumors (GSTs), which are a rare disease that begins in the walls of the GI tract. Gleevec® is currently the standard drug treatment for patients with GSTs, however, drug resistance occurs in most patients within 2 years of treatment. The team, led by Anette Duesing, screened 89 FDAapproved chemotherapeutic agents to identify new therapeutic agents for patients who develop resistance
to conventional treatments. The results indicated that transcriptional inhibitors and topoisomerase II have promising anticancer activity against GST cells. Specifically, mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor demonstrated the most promising anticancer potential, which had previously been used to treat metastatic breast cancer and leukemia, respectively. In terms of future development, Duensing commented, “The next step will be moving our findings to clinical exploration to see if the results we found in the laboratory hold up in patients.”
– Written by Jessica Thorne Sources: Boichuk S, Lee DJ, Mehalek KR et al. Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res. doi:10.1158/0008-5472.can-13-1955 (2014) (Epub ahead of print); Laboratory detective work points to potential therapy for rare, drug-resistant cancer: www.upmc.com/media/ NewsReleases/2014/Pages/upci-scientists-detect-therapy-for-drug-resistant-cancer.aspx
602
Future Med. Chem. (2014) 6(6)
future science group
News and Analysis
Promising strategy developed to target drug-resistant cancer cells Researchers from the Karolinska Institutet (Stockholm, Sweden) and Uppsala University (Uppsala, Sweden) have reported a promising strategy to target drug-resistant cancer cells, by inducing mitochondrial dysfunction. The study identified a novel therapeutic agent, termed VLX600, which demonstrated promising anticancer activities. A current challenge faced during cancer drug discovery is the ability to target dormant cancer cells, which are often resistant to conventional treatments. In the present study, the team demonstrated that dormant cells, which are found in oxygen deficient microenvironments, are sensitive to disturbances in mitochondrial function. Screening and validation experiments identified the small molecule, VLX600, which was able
to reduce the viability of dormant cells in vivo. VLX600-induced mitochondrial dysfunction by increasing glycolysis through inhibition of mitochondrial oxidative phosphorylation. Due to the oxygendeficient microenvironment in which the dormant cells reside, the team hypothesize that they are particularly sensitive disturbances in mitochondrial function. The team reported in their conclusion, “Since conventional cytotoxic anticancer agents are significantly less effective under conditions of nutrient depletion, this type of mechanism will be interesting to exploit for therapy.” VLX600 is currently in development to start Phase I clinical trials in patients with solid tumors.
– Written by Jessica Thorne Source: Zhang X, Fryknäs M, Hernlund E et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat. Commun. doi:10.1038/ncomms4295 (2014) (Epub ahead of print).
Unified multiscale simulation software developed A group of scientists from the University of California San Diego (CA, USA) have developed a simple and unified multiscale simulation software for computational-aided drug design. The team, led by Andreas Götz and Ross Walker, developed a unified interface for quantum mechanical and classical molecular mechanical dynamic simulations using the AMBER molecular dynamics software package. Speaking to Future Medicinal Chemistry, Walker explained that the software developed allows users to “select the optimum quantum package for a given problem, without having to study the intricacies of the interface for each program.” Commenting on the significance of the study, Walker explained that the new software will enable researchers to carry out direct simulations of chemical reactions in enzymes, which is beneficial as it eliminates the need to make gross approximations, which can induce error. Furthermore, Walker commented “Depending on the requirements it provides a way to seamlessly run such calculations on a variety of hardware ranging from desktops to large HPC
resources and even GPU accelerated machines. Ultimately it provides a next generation computational tool for understanding and predicting the behavior of molecular systems at a fundamental level.” Walker concluded, “This has applications for next generation drug design and delivery, better chemicals, materials and biocatalysis.”
“
...the new software will enable researchers to carry out direct simulations of chemical reactions in enzymes, which is beneficial as it eliminates the need to make gross approximations, which can induce error.
”
The team are planning to further develop the software by adding support for additional quantum packages and more accurate and flexible multiscale coupling schemes. Additionally, the group are also involved in tailoring and optimizing the interface for San Diego Supercomputer Center’s launch of the next generation supercomputer ‘Comet.’
– Written by Jessica Thorne Source: Götz AW, Clark MA, Walker RC. An extensible interface for QM/MM molecular dynamics simulations with AMBER. J. Comput. Chem. doi:10.1002/jcc.23444 (2014) (Epub ahead of print).
future science group
www.future-science.com
603
Future
Medicinal Chemistry
Electrically controlled drug-delivery system may help minimize side effects Remotely controlled drug-delivery device may be a step towards ‘smart’ closed-loop drug-eluting systems
Researchers from the University of Pittsburgh (PA, USA) have developed an electrically controlled drug-delivery nanocomposite that is able to release the drug on-demand in response to voltage stimulation. The nanocomposite comprises graphene oxide (GO) deposited inside a conducting polymer scaffold, which was found to exhibit favorable electrical properties. The team loaded the drug-delivery system with anti-inflammatory molecule, dexamethasone. When voltage stimulation was applied, the nanocomposite was found to Eventually, we wish to build release the drug with a linear release profile a close-loop system, which detects a condition and releases at a dosage that could be adjusted by varying the magnitude of stimulation. In the treatment accordingly. absence of stimulation, it was observed that the drug did not passively diffuse from the composite. The group, which was led by Xinyan Tracy Cui, Associate Professor at the University of Pittsburgh, reported that they were able to tailor the properties of the delivery system by decreasing the size and thickness of the GO nanosheets, which in turn influenced drug loading and release profiles. In addition, in vitro cell culture experiments demonstrated that the released drug retained its bioactivity and that no toxic byproducts were leached from the film during electrical stimulation. According to the team, previous versions of the drug-release system were severely
“
”
part of
10.4155/FMC.14.33 © 2014 Future Science Ltd
limited by a finite drug-loading capacity. However, with the addition of the GO nanosheets to the nanocomposite material it was found that the amount of drug that could be released from the system significantly improved, thereby widening the therapeutic range of the device and potentially increasing its lifespan. Commenting on the significance of the results, Cui explained that, conventionally, drugs are delivered systemically (for example orally or intravenously), at a dose that is much higher than that which is required to have a therapeutic effect at the target tissue, often resulting in adverse side effects. Cui commented, “With our on-demand delivery system, these side effects may be avoided because we will be able to release the drug selectively into the target tissue, with a high level of control over the timing of delivery and the magnitude of the dose.” Speaking to Future Medicinal Chemistry, Cui commented that, in terms of future work the team intends to, “continue investigating the ability of the GO nanosheets to finely modulate the dosing range of the drug-delivery system.” The team also plans to study the sensing capability of the composite to detect various biomarkers or neural signals. “Eventually, we wish to build a close-loop system, which detects a condition and releases treatment accordingly,” said Cui.
– Written by Hannah Coaker Source: Weaver CL, Larosa JM, Luo X, Cui XT. Electrically controlled drug delivery from graphene oxide nanocomposite films. ACS Nano. 8 (2), 1834–1843 (2014).
Future Med. Chem. (2014) 6(6), 601–603
ISSN 1756-8919
601
News and Analysis News
New compound could be an ideal candidate for visual restoration in patients with degenerative retinal disorders Millions of people suffer from progressive degeneration of their rods and cones, specialized photoreceptor cells in the outer retina that convert light into visual signals, transmitted to the brain via retinal ganglion cells (RGCs). This degeneration can lead to blindness; however, RGCs typically remain functional even after death of the rods and cones.
“
...favorable spectral sensitivity and selective targeting make DENAQ a prime candidate for visual restoration in patients in degenerative retinal diseases.
”
Now, a team of scientists from the University of California, Berkeley (CA, USA) have reported the temporary restoration of visual function to blind mice, following the intraocular injection of a small molecule, DENAQ. Led by Richard Kramer, professor of neurobiology at the university, the group had previously demonstrated that DENAQ, a photoswitch chemical that changes its conformation in response to light, could confer light sensitivity on certain voltage
gated ion channels. In this latest paper, the researchers tested the action of the small-molecule compound on 3–6 month-old mice carrying a mutation that causes their rods and cones to degenerate within 1 month. By recording neuronal activity from the RGCs using an electrode array, their findings showed that RGCs from the diseased mice conferred strong light sensitivity following treatment with DENAQ. The work studied the effects of the compound on functional, non-functional and degenerated rods and cones, demonstrating that DENAQ only acts on RGCs if the rods and cones have already died. This suggests that degeneration in the outer retina leads to electrophysiological changes in the inner retina, thus allowing DENAQ photosensitization. However, the presence of intact photoreceptors prevents the action of the compound. This selective action may reduce side effects on healthy retina, and, while further studies are required before human trials for the compound, the favorable spectral sensitivity and selective targeting make DENAQ a prime candidate for visual restoration in patients in degenerative retinal diseases.
– Written by James Potticary Source: Tochitsky I, Polosukhina A, Degtyar VE et al. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron doi:10.1016/j.neuron.2014.01.003 (2014) (Epub ahead of print).
Drug repurposing identifies therapeutic agents for gastrointestinal stromal tumors A team of researchers from the University of Pittsburgh Cancer Institute (PA, USA) have discovered potential new uses for two US FDA-approved anticancer drugs for the treatment of gastrointestinal stromal tumors (GSTs), which are a rare disease that begins in the walls of the GI tract. Gleevec® is currently the standard drug treatment for patients with GSTs, however, drug resistance occurs in most patients within 2 years of treatment. The team, led by Anette Duesing, screened 89 FDAapproved chemotherapeutic agents to identify new therapeutic agents for patients who develop resistance
to conventional treatments. The results indicated that transcriptional inhibitors and topoisomerase II have promising anticancer activity against GST cells. Specifically, mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor demonstrated the most promising anticancer potential, which had previously been used to treat metastatic breast cancer and leukemia, respectively. In terms of future development, Duensing commented, “The next step will be moving our findings to clinical exploration to see if the results we found in the laboratory hold up in patients.”
– Written by Jessica Thorne Sources: Boichuk S, Lee DJ, Mehalek KR et al. Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res. doi:10.1158/0008-5472.can-13-1955 (2014) (Epub ahead of print); Laboratory detective work points to potential therapy for rare, drug-resistant cancer: www.upmc.com/media/ NewsReleases/2014/Pages/upci-scientists-detect-therapy-for-drug-resistant-cancer.aspx
602
Future Med. Chem. (2014) 6(6)
future science group
News and Analysis
Promising strategy developed to target drug-resistant cancer cells Researchers from the Karolinska Institutet (Stockholm, Sweden) and Uppsala University (Uppsala, Sweden) have reported a promising strategy to target drug-resistant cancer cells, by inducing mitochondrial dysfunction. The study identified a novel therapeutic agent, termed VLX600, which demonstrated promising anticancer activities. A current challenge faced during cancer drug discovery is the ability to target dormant cancer cells, which are often resistant to conventional treatments. In the present study, the team demonstrated that dormant cells, which are found in oxygen deficient microenvironments, are sensitive to disturbances in mitochondrial function. Screening and validation experiments identified the small molecule, VLX600, which was able
to reduce the viability of dormant cells in vivo. VLX600-induced mitochondrial dysfunction by increasing glycolysis through inhibition of mitochondrial oxidative phosphorylation. Due to the oxygendeficient microenvironment in which the dormant cells reside, the team hypothesize that they are particularly sensitive disturbances in mitochondrial function. The team reported in their conclusion, “Since conventional cytotoxic anticancer agents are significantly less effective under conditions of nutrient depletion, this type of mechanism will be interesting to exploit for therapy.” VLX600 is currently in development to start Phase I clinical trials in patients with solid tumors.
– Written by Jessica Thorne Source: Zhang X, Fryknäs M, Hernlund E et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat. Commun. doi:10.1038/ncomms4295 (2014) (Epub ahead of print).
Unified multiscale simulation software developed A group of scientists from the University of California San Diego (CA, USA) have developed a simple and unified multiscale simulation software for computational-aided drug design. The team, led by Andreas Götz and Ross Walker, developed a unified interface for quantum mechanical and classical molecular mechanical dynamic simulations using the AMBER molecular dynamics software package. Speaking to Future Medicinal Chemistry, Walker explained that the software developed allows users to “select the optimum quantum package for a given problem, without having to study the intricacies of the interface for each program.” Commenting on the significance of the study, Walker explained that the new software will enable researchers to carry out direct simulations of chemical reactions in enzymes, which is beneficial as it eliminates the need to make gross approximations, which can induce error. Furthermore, Walker commented “Depending on the requirements it provides a way to seamlessly run such calculations on a variety of hardware ranging from desktops to large HPC
resources and even GPU accelerated machines. Ultimately it provides a next generation computational tool for understanding and predicting the behavior of molecular systems at a fundamental level.” Walker concluded, “This has applications for next generation drug design and delivery, better chemicals, materials and biocatalysis.”
“
...the new software will enable researchers to carry out direct simulations of chemical reactions in enzymes, which is beneficial as it eliminates the need to make gross approximations, which can induce error.
”
The team are planning to further develop the software by adding support for additional quantum packages and more accurate and flexible multiscale coupling schemes. Additionally, the group are also involved in tailoring and optimizing the interface for San Diego Supercomputer Center’s launch of the next generation supercomputer ‘Comet.’
– Written by Jessica Thorne Source: Götz AW, Clark MA, Walker RC. An extensible interface for QM/MM molecular dynamics simulations with AMBER. J. Comput. Chem. doi:10.1002/jcc.23444 (2014) (Epub ahead of print).
future science group
www.future-science.com
603
