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PI3K Inhibitor CUDC-907 Suppresses Growth of MYC-dependent Cancers

MYC is a frequently deregulated oncogene in many human cancers. It is normally responsible for facilitating cell growth and proliferation through the encoding of transcription factors. Since many types of cancers are dependent on the upregulation of MYC, reducing MYC protein levels by targeting its upstream regulators such as histone deacetylases (HDAC) and phophoinositide 3-kinases (PI3K) may be a viable and effective method of treatment.

CUDC-907 is an inhibitor of PI3K and class I and II HDACs. In a recent study published in Molecular Cancer Therapeutics, it was shown that PI3K and HDAC inhibition synergistically downregulated MYC protein levels and induced apoptosis in “double-hit” (DH) diffuse large B-cell lymphoma (DLBCL) cells. CUDC-907 suppressed the growth and survival of MYC-altered or MYC-dependent cancer cells through this downregulation of the MYC protein. Further research and development utilizing CUDC-907 in MYC-driven cancers may be pursued thanks to this study.

LKT Laboratories carries CUDC-907 as well as a number of other PI3K inhibitors for research use.

C8112 CUDC-907

PI3K inhibitor list

 

 

Kaiming S., Ruzanna A., et al. Dual HDAC and PI3K inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers. Mol Cancer Ther 2016.

Cabozantinib Shows Activity in Human Gastrointestinal Stromal Tumor Models

Cabozantinib is a chemotherapeutic compound that has shown potential as a treatment for medullary thyroid cancer and other types of solid tumors. It is primarily known for its inhibition of c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2). By inhibiting these tyrosine kinases Cabozantinib reduces tumor growth, metastasis, and angiogenesis.

In a 2016 study, cabozantinib showed activity against gastrointestinal stromal tumors (GIST). In many cases of GIST, oncogenic signaling is driven by KIT mutations. Tyrosine kinase inhibitors (TKI) such as imatinib have been used to treat GIST, but resistance to TKI caused by secondary mutations to KIT sometimes renders this treatment ineffective.

Cabozantinib was tested in patient-derived xenograft models of GIST, with each model carrying different KIT mutations. Three different models were examined in total, and in all three cabozantinib inhibited proliferative activity, even in those models that were imatinib-resistant. Compared to an imatinib treated group and a control group, cabozantinib also significantly reduced microvessel density in all three models.

From the study it was concluded that cabozantinib shows promising antitumor activity in both imatinib-sensitive and imatinib-resistant GIST models. The activity is achieved through the inhibition of tumor growth, proliferation, and angiogenesis, and may provide a valid alternate treatment method for GIST going forward.

C0006 Cabozantinib

I4802 Imatinib Mesylate

Gebreyohannes Y., Schoffski P., et al. Cabozantinib is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations. Mol Cancer Ther; 15(12); 2845-52.

Piperlongumine Suppresses Pancreatic Tumor Growth

Piperlongumine is found in several species of the Piper plant and displays many beneficial characteristics, including antithrombotic, anti-inflammatory, anti-atherosclerotic, and chemotherapeutic activities. Isolated from the fruit of the long pepper, recent research has focused on the ability of this natural product to suppress tumor growth alone and in combination with other chemotherapeutic compounds.

In a study published in 2015, the effects of Piperlongumine were examined in pancreatic cancer cells. Pancreatic cancer is an aggressive malignancy with a relatively poor prognosis, even in cases where it is diagnosed early. There are few good options for chemotherapy.

In vitro, piperlongumine showed inhibition of pancreatic cancer cell lines, inhibited the activation of NF-kB, and also potentiated the apoptotic effects of gemcitabine, a nucleoside analog commonly used in the chemotherapeutic treatment of some cancers. Piperlongumine went on to show significant activity in vivo, where it suppressed tumor growth alone and enhanced the efficacy of gemcitabine in xenograft mouse models. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation, and increased apoptosis in tumor remnants seen in the model.

The results of the study suggest both potential for piperlongumine as a stand-alone treatment for human pancreatic cancer, as well as a partner-chemotherapeutic with compounds like gemcitabine. Both piperlongumine and gemcitabine are available from LKT Labs for research use.

P3561 Piperlongumine

G1745 Gemcitabine Hydrochloride

Wang Y., Wu X., et al. Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway. Cancer Prev. Res. Mar;9(3):234-44.

LKT earns MBE Certification from the National Minority Supplier Development Council

As of October 12th, 2016, LKT Laboratories has earned its MBE certification from the North Central Minority Supplier Development Council. The National Minority Supplier Development Council (NMSDC) advances business opportunities for certified minority business enterprises and is one of the nation’s leading corporate membership organizations.

End users may secure funding for resources provided by trusted minority-owned businesses such as those certified through the NMSDC. LKT Labs is proud to join this network of organizations.

Aurora Kinase B Inhibitor Barasertib Inhibits Growth of Small-cell Lung Cancer Lines

Barasertib, also known as AZD-1152, is a highly selective aurora kinase B inhibitor. As an aurora kinase inhibitor, it has shown the ability to disrupt the cell cycle and consequently induce apoptosis in vitro. It has inhibited the growth of human colon, lung, and haematologic tumor xenografts in immunodeficient mice, and continues to be evaluated in various disease models.

In a 2016 study, barasertib inhibited the growth of small-cell lung cancer cells in vitro and in vivo. Small-cell lung cancer cells are good targets for aurora kinase inhibition, thanks to their rapid proliferation and high rates of MYC family amplification. Inhibitors of mitosis such as aurora kinase inhibitors have been effective in causing apoptosis in cells expressing high levels of MYC in other tumor types.

A panel of small-cell lung cancer lines with and without MYC family gene amplification was screened for growth inhibition by barasertib. The growth inhibition caused by barasertib correlated with cMYC amplification and cMYC gene expression in the panel. Small-cell lung cancer tumors with high cMYC amplification or gene expression may thus be good targets for barasertib and other aurora kinase B inhibitors.

LKT Labs sells a number of aurora kinase inhibitors, including AZD1152:

A9714 AZD-1152-HQPA

M4652 MLN-8237

T5996 Tozasertib

Z4900 ZM-447439 Trihydrate

References:

Helfrich B., Kim J., et al. Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLS Cell Lines In Vitro and In Vivo. Mol Cancer Ther; 15(10); 2314-22. PMID: 27496133.

Welcome to the new lktlabs.com!

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Welcome to the new lktlabs.com! The long process of updating and improving our website has come with one focus in mind: improving the customer experience.
LKT Labs understands that finding the particular compounds relevant to your research can be difficult, which is why search-ability and organization was emphasized at each stage. All 3,000 different small molecule biochemicals have been organized into over 700 categories to help you better find the products you are looking for. The improved categorization includes sorting by various research areas, mechanisms of action, and targets. On the left side of each category page you will find a new category tree menu containing the many tiers of product groupings. Navigation to each LKT’s core products can be accessed via the “Products” dropdown menu at the top of every page, or the research category buttons below the banner on the home page. The search function is also improved and will help to locate products through a broader range of terms.
Improving the customer experience also means enhancing the amount of product information available for our customers. Each product page now displays stock status and is updated in real time, so you know if the item you are looking for can be shipped immediately. Keeping products in stock is what LKT Labs strives for, but when products are out of stock you’ll be aware right away. Important product documents are now available for download, including brochures, safety data sheets, and product information sheets. All pages are mobile friendly so it doesn’t matter what device you are browsing on.
There are new pages highlighting the various services offered by LKT, including custom synthesis and natural product isolation. Expanded support forms to make it easier for you to get specific answers to your questions as soon as possible. Have a suggestion for the site? Let us know what you want to see.
Online ordering has never been easier and account pages are improved for your convenience. Ordering is straight forward and fast. You are now able to get the tracking number and invoice for your order, as well as see what you ordered last time from your account page. Try out our new online ordering process and enter promo code NEWSITE for a celebratory 15% off! It’s our way of saying, “Welcome to the new lktlabs.com”.

Sulforaphane suppresses tumor development in triple-negative breast cancer

brocolli-smallTriple-negative breast cancer (TNBC), so named for its lack of expression of the genes for estrogen receptor, progesterone receptor, and Her2/neu, is a breast cancer subtype with a poor prognosis that is difficult to treat. Sulforaphane, an abundant dietary component found in broccoli, has been shown to inhibit cell proliferation and sphere formation of the cancer stem cell population in TNBC cells.

In a study at the National Cancer Institute in Bethesda, an isolated population of cancer stem cells were treated with Sulforaphane. They subsequently lost the ability to form mammospheres in vitro. An in vivo study showed a decrease in tumor volume when BalbC/nude mice were supplemented with Sulforaphane before and after cell inoculation. When treatment started before tumor implantation, a higher suppressive effect of Sulforaphane was seen, indicating that Sulforaphane may also be an effective chemopreventive agent.

The non-toxicity and general availability of Sulforaphane as a natural product, combined with the efficacy seen in the work noted above, make it a good candidate for continued study in TNBC.

LKT manufactures and isolates both synthetic and natural forms of Sulforaphane, as well as many other isothiocyanate compounds.

Isothiocyanates:

S8044 R,S Sulforaphane
S8046 R-Sulforaphane
S8049 S-Sulforaphene
B1653 Benzyl Isothiocyanate

References:
Castro N, Rangel M, Salomon D, et al. Sulforaphane suppresses the growth of triple-negative breast cancer stem-like cells in vitro and in vivo. Cancer Res 2016;75(15 Suppl):Abstract nr 912.

Dabrafenib and Other Raf Inhibitors

Dabrafenib

Raf proteins are serine/threonine kinases that transduce signals from Ras proteins and amplify them using the MAPK signaling cascade. Mutant forms of B-Raf, one of the primary types of Raf proteins, play a significant role in the development of many cancers.

The mutations that occur in B-Raf, such as V599K or V600E destabilize the protein’s regular interactions, inducing activation and resulting in potentially uncontrolled downstream signaling and cell growth. As a result, the Ras-Raf signaling pathway has become a very interesting target for anticancer chemotherapeutic compounds.

Dabrafenib is a reversible kinase inhibitor that is selective for mutant (V600E) B-Raf. It is an ATP-competitive inhibitor that has been used in the treatment of unresectable or metastatic melanomas, and also shows potential in the treatment of brain metastases. In a 2016 study, results from a phase II trial showed that dabrafenib exhibited significant activity in patients with advanced non-small cell lung cancer harboring the V600E B-Raf mutation. The study also suggested that combining dabrafenib with a MEK inhibitor might be an even more effective treatment for patients with this type of cancer.

LKT Labs sells a number of high purity B-Raf inhibitors, including the following compounds:

D0004 Dabrafenib

P0397 Pazopanib

P1200 PD184352

S0459 SB590885

V1668 Vemurafenib

Dabrafenib Active in Rare NSCLC Subtype.  Cancer Discov. 2016 Jul;6(7):OF4.  PMID: 27207893.

Diallyl Disulfide Displays Chemopreventive Activity through GSK-3β Inhibition

GarlicSulfur-containing compounds isolated from garlic, known for their anti-inflammatory properties, are exhibiting chemopreventive effects in recent research by the National Cancer Institute. Diallyl Disulfide (DADS) is one such compound. DADS was shown to prevent colorectal tumorigenesis in a mouse model of colitis-induced colorectal cancer.

In this study, mice treated with the chemical carcinogen azoxymethane, as well as the colonic irritant dextran sodium sulfate, were then supplemented with DADS. The result was a reduction in tumor incidence, tumor number, and tumor burden compared to the control group. The DADS diet was also shown to resolve initial dextran sodium sulfate-induced inflammation faster than the control diet, resulting in a shortened period of inflammation and cellular transformation.

In vitro studies on the mechanism of action at work suggest that the chemopreventive effects shown by DADS are mediated through NF-kB signaling. NF-kB nuclear localization and activity were diminished in colorectal cancer cells treated with DADS. The study stated that the NF-kB suppression was dependent on DADS inhibition of GSK-3ß, and that these results were seen bothin vitro and in vivo.

DADS is just one of the many interesting sulfur-containing compounds found in garlic. LKT Labs isolates or manufactures a number of these products, including the following:

A4440 Allicin

A4544 Diallyl Disulfide

D3202 Diallyl Trisulfide

D3203 Diallyl Tetrasulfide

Saud SM, Li W, et al., Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-kB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3b. Cancer Prevention Research. 2016. PMID: 27138790

DNMT and HDAC Inhibition Block the Rise of Tumor Growth in Cancer Stem-like Cells

A study published in 2015 found that breast cancer stem cells are intrinsically sensitive to both genetic and epigenetic modifications and are therefore susceptible to epigenetic based therapies. Combined inhibition of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) may prove a potent route to prevent tumorigenicity in this and other cancer models.

In this study, the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate  reduced the abundance of cancer stem cells while increasing the overall survival rate in a mouse model. Further analysis indicated that the 5-azacytidine plus butyrate therapy blocked growth-promoting signaling molecules such as RAD51AP1 and SPC25 through the inhibition of chromatin modifiers. These signaling molecules are important in DNA damage repair and kinetochore assembly, and are significantly over expressed in human breast tumor tissues.

Epigenetic modifiers are a promising group of compounds that have seen a large rise in research focus over the past decade. LKT Labs carries a number of DNMT and HDAC  inhibitors, in addition to other epigenetic modifiers. A  small selection of these popular small molecules are below:

A9602 Azacitidine

E5477 Entinostat

M3476 Mithramycin

T6933 Trichostatin A

V5734 Vorinostat

Pathania R, Ramachandran S, et al., Combined inhibition of DNMT and HDAC blocks the tumorigenicity of cancer stem-like cells and attenuates mammary tumor growth. Cancer Res. 2016 April.

Aromatase inhibitors may be an effective treatment for status epilepticus

In an animal study performed at Northwestern University in 2016, estrogen synthesis was identified as a previously unknown factor in the escalation of seizures. This finding provides new potential for a class of molecules known as aromatase inhibitors, which prevent a process known as aromatization that allows the conversion of androgens into estrogens. Aromatase inhibitors may now be relevant in studies on the treatment of status epilepticus, which occurs when seizures last too long or occur close together without the opportunity for recovery in between.

Status epilepticus was induced in a group of rats by kainic acid. The study found this action stimulated estradiol synthesis in the hippocampus. The hippocampus is commonly involved in seizures, and estradiol is known to acutely promote neural activity in that region of the brain. Higher estradiol levels were seen in rats experiencing more severe seizures. Through the administration of aromatase inhibitors after seizure onset, both electrographic and behavioral seizures were strongly suppressed. The result suggests that neurosteroid estrogen synthesis may contribute to the escalation of seizures and that the administration of aromatase inhibitors may be an effective treatment.

LKT Labs carries a number of aromatase inhibitors, including the following:

A5302 Anastrozole
C5680 Coumestrol
E9317 Exemestane
L1878 Letrozole

View a full list of the aromatase inhibitors LKT carries here.

CDK4/6 Inhibitor Palbociclib Induces Therapeutic Senescence in Melanoma Cells

The p16-cyclin D1-CDK4/6-Rb pathway is dysregulated in a large percentage of melanomas and has become an interesting target for the therapeutic treatment of this disease. CDK4 activation results in the inhibition of the retinoblastoma protein that leads to G1-S cell-cycle transition, and also phosphorylates other proteins that promote cell-cycle progression and inhibit apoptosis and senescence in the cell. It is thought that melanomas with activating events in the CDK4 pathway may become overly dependent on it, in which case inhibition of CDK4 would go beyond the induction of cell-cycle arrest to apoptosis and tumor regression.

In a study published in March of 2016, palbociclib, a specific CDK4/6 inhibitor, was shown to induce cell cycle arrest and eventual senescence in melanoma cells. Furthermore, palbociclib was found to maintain its effectiveness even in tumors resistant to vemurafenib, a specific BRAF(V600E) inhibitor. Vemurafenib has shown significant clinical efficacy in BRAF(V600E)-positive melanomas, but rapid resistance by the tumor to the compound has hampered its impact.

These findings suggest that palbociclib may be a promising therapeutic for the treatment of melanoma, and that a treatment path involving vemurafenib followed by palbociclib may yield an effective treatment for the vemurafenib-resistant metastatic disease. The CDK4/6 pathway and its inhibitors will continue to be investigated for their role in melanoma and tumor development and suppression.

LKT Labs supplies research grade palbociclib and vemurafenib, in addition to other CDK4/6 inhibitors.

P0244 Palbociclib Hydrochloride
R5774 Roscovitine
O4556 Olomoucine
I5212 Indirubin

Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013 Oct 1;19(19):5320-8. doi: 10.1158/1078-0432.CCR-13-0259. PMID: 24089445

Yoshida A, Lee EK, Diehl JA. Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6. Cancer Res. 2016 May 15;76(10):2990-3002. doi: 10.1158/0008-5472.CAN-15-2931. Epub 2016 Mar 17. PMID: 26988987

Inhibition of vacuolar-type ATPase suppresses breast cancer cell survival

Vacuolar-type ATPases (V-ATPases) couple ATP hydrolysis and proton transport across membranes in eukaryotic cells. This regulation of the protein gradient often plays a role in driving Ca2+ gradients, maintaining pH homeostasis, and stimulating HCO3- reabsorption. V-ATPases may also play a role in tumor biology. Hypoxic conditions often occur during the development of solid tumors, leading to acidosis, which can induce DNA damage. To prevent intracellular acidosis and its negative downstream effects, tumor cells may upregulate expression of pH regulators such as V-ATPases as a way to remove protons from tumor cells.

An article recently published in Cancer Research highlights V-ATPases as a potential target to suppress tumor growth. Inhibition of these enzymes triggered metabolic stress by interfering with HIF-1α signaling and iron metabolism. As a result, cell cycle progression halted and apoptosis was induced, preventing growth of breast cancer cells.

The results from this study indicate the potential for V-ATPase inhibition in the treatment of cancers and suggest further research exploration of this mechanism in cellular and animal models.

For more information on the original study, click here.

LKT carries several compounds that alter vacuolar-type ATPase activity! Click the representative links below for more information.

References:

Schneider LS, von Schwarzenberg K, Lehr T, et al. Vacuolar-ATPase Inhibition Blocks Iron Metabolism to Mediate Therapeutic Effects in Breast Cancer. Cancer Res. 2015 Jul 15;75(14):2863-74. PMID: 26018087.

Izumi H, Torigoe T, Ishiguchi H, et al. Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 2003 Dec;29(6):541-9. PMID: 14585264.

Reversing latent HIV infection with disulfiram

Disulfiram (D3374) is an acetaldehyde dehydrogenase inhibitor that prevents alcohol metabolism and is used to treat chronic alcohol dependence. Disulfiram has been used for this purpose for many decades. Recently, a strong movement is in place to find new indications for already-marketed compounds. Finding new uses for compounds that are already marketed allows for quicker advancement through pre-clinical and clinical work, as much of the required safety data is already available.

Disulfiram is one of the many compounds that have experienced resurgences in research studies going beyond their initial usage. In an article published in Lancet HIV, disulfiram was shown to have effects in HIV models. One challenge with HIV treatment is that latent (dormant) virus is often difficult to remove, as many current therapies focus on preventing replication or entry of active viral particles but are not effective against the virus in its latent form. In this study, short-term administration of disulfiram activated HIV transcription and increased plasma HIV RNA in a clinical setting.

Disulfiram may therefore show benefit when combined with current HIV therapies as it may “flush out” and induce activation of latent virus, allowing antivirals to attack more effectively.

If you are working on latent or active HIV research models, check out our library of HIV-focused antivirals!

For more information on the original study, click here.

References:

Elliott JH, McMahon JH, Chang CC, et al. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV. 2015 Dec;2(12):e520-9. PMID: 26614966.

Discovery of DNA repair mechanisms: A summary of the findings behind the 2015 Nobel Prize in Chemistry

Recently, the Nobel Assembly announced the winners of the 2015 Nobel Prize in Chemistry. The award is focused around the discovery of three different mechanisms behind DNA repair. Tomas Lindahl was awarded one third of the prize for his work on base excision repair. Paul Modrich awarded one third of the prize for studies on mismatch repair. Aziz Sancar was also awarded one third of the prize for his discovery of nucleotide excision repair.

Tomas Lindahl initially started his research career by finding that DNA has limited chemical stability, partially due to spontaneous chemical reactions that occur on DNA bases. Lindahl identified E. coli uracil-DNA glycosylase and 3-methyladenine glycosylase, two proteins involved in base excision repair. In the following years, he outlined a model detailing how DNA glycosylases recognize and cleave the base-deoxyribose glycosyl bonds of damaged nucleotides, flip and release the nucleotide, and then facilitate its replacement by other enzymes, including endonuclease, DNA polymerase, and DNA ligase.

Paul Modrich was one of the first scientists to provide direct evidence for mismatch repair. Modrich also developed an assay to allow analysis of DNA mismatch repair in E. coli using bacteriophage heteroduplexes with mismatches that could be recognized by two different restriction endonucleases. With this assay, he showed that repair activity was ATP-dependent, indicated heteroduplex methylation states, and highlighted how mutations in mutH, mutL, mutS, and mutD impair mismatch repair. Later, Modrich explored further variations in mismatch repair using other cellular models and studying how the process differs on leading versus lagging DNA strands.

Aziz Sancar followed up on previous theories regarding repair mechanisms that correct UV-induced lesions by identifying proteins involved in these processes. Sancar developed a technique that allowed for labeling and detection of proteins encoded by a plasmid of interest in a background free of other components. This technique was used to identify proteins encoded by uvrA, uvrB, and uvrC involved in nucleotide excision repair. Sancar used these proteins to determine several steps in the correcting of UV-induced thymine dimers, one of many lesions recognized and amended by nucleotide excision repair processes.

For more information on the 2015 Nobel Prize in Chemistry, click here.

LKT carries several compounds that alter DNA repair machinery! For more information on these, please click the representative links below.

PARP inhibitors:

ATM/ATR kinase inhibitors:

MGMT inhibitors:

References:

Mol CD, Arvai AS, Slupphaug G, et al. Crystal structure and mutational analysis of human uracil-DNA glycosylase: structural basis for specificity and catalysis. Cell. 1995 Mar 24;80(6):869-78. PMID: 7697717.

Lahue RS, Au KG, Modrich P. DNA mismatch correction in a defined system. Science. 1989 Jul 14;245(4914):160-4. PMID: 2665076.

Lu AL, Clark S, Modrich P. Methyl-directed repair of DNA base-pair mismatches in vitro. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4639-43. PMID: 6308634.

Sancar A, Rupp WD. A novel repair enzyme: UVRABC excision nuclease of Escherichia coli cuts a DNA strand on both sides of the damaged region. Cell. 1983 May;33(1):249-60. PMID: 6380755.

Sancar A, Hack AM, Rupp WD. Simple method for identification of plasmid-coded proteins. J Bacteriol. 1979 Jan;139(1):692-3. PMID: 368040.

Lindahl T. New class of enzymes acting on damaged DNA. Nature. 1976 Jan 1-8;259(5538):64-6. PMID: 765833.

Lindahl T. An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci USA. 1974 Sep;71(9):3649-53. PMID: 4610583.

Discovery of therapies against parasitic diseases: A summary of the findings behind the 2015 Nobel Prize in Medicine

Recently, the Nobel Assembly announced the winners of the 2015 Nobel Prize in Medicine. The award is focused around the discovery of therapies against parasitic diseases. One half of the award went to Professor Youyou Tu for her studies on artemisinin and the other half went jointly to Dr. William C. Campbell and Professor Satoshi Ōmura for their research on avermectins.

Professor Youyou Tu discovered that the plant Artemisia annua had been used in many traditional Chinese medicine recipes for the treatment of malaria. Using historical texts to devise an extraction method, Tu was able to isolate artemisinin from the plant leaves. This compound was highly effective in killing Plasmodium, a malaria-carrying parasite, in various animal models. Since this finding, artemisinin and its derivatives have been used successfully to reduce the mortality rate of malaria infection by nearly half worldwide. Artemisinin is thought to kill parasites by increasing levels of reactive oxygen species and inducing oxidative stress.

Professor Satoshi Ōmura used his background in natural product isolation to isolate and characterize a new strain of Streptomyces. This new strain was found in soil near a golf course in Japan and upon characterization, was found to exhibit antimicrobial activity. The bacterial culture was sent to Dr. William C. Campbell to explore its efficacy in animal models of parasitic infection. After Ōmura refined the culturing conditions for the bacteria, Campbell characterized the active component avermectin B1. A semi-synthetic derivative of this compound, ivermectin, was examined in further animal and clinical studies, showing efficacy against a variety of worms and nematodes. Although the mechanism of action is unknown, it is thought to involve glutamate-gated chloride channels and GABA-activated chloride channels.

For more information on the 2015 Nobel Prize in Medicine, click here

LKT carries several avermectins and artemisinin-related compounds! For more information on these, please click the representative links below.

References:

Estrada-Mondragon A, Lunch JW. Functional characterization of ivermectin binding sites in α1β2γ2L GABA(A) receptors. Front Mol Neurosci. 2015 Sep 25;8:55. PMID: 26441518.

Ōmura S. Microbial metabolites: 45 years of wandering, wondering and discovering. Tetrahedron. 2011; 67: 6420-59.

Cui L, Su X. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther. 2009 Oct; 7(8): 999-1013. PMID: 19803708

Tu YY. The constituents of young Artemisia annua. Zhong Yao Tong Bao. 1985 Sep;10(9):35-6, 18. PMID: 2935314.

Small molecule regulation of SK channels

Small conductance Ca2+-activated K+ (SK) channels are a small family of ion-gated K+ channels involved in synaptic plasticity, which is a key process in learning and memory. These channels are controlled primarily by changes in the concentration of intracellular calcium through opening and closing of N-type calcium channels. Ca2+ bound to calmodulin directly binds the C-terminus of the channel, changing its conformation. SK channels can be found throughout the central nervous system where they manage neuronal action potential discharge frequency.

Recently, an article published in Science Advances highlights the role of phosphatidylinositol 4,5-bisphosphate (PIP2) as a modulator of SK channel activity. PIP2 is a known cofactor involved in regulation of many ion channels, although its role in respect to SK channels had previously been undetermined. In this study, scientists used SK channel inhibitors to examine the role of PIP2. Results indicated that PIP2 chaperones the binding of the Ca2+-calmodulin complex to the channel, facilitating channel opening and closing.

This study highlights the role of PIP2 in SK channel regulation, suggesting a new target – that of the PIP2-SK channel interaction – in the development of new SK channel activators and blockers, compounds that may show benefit in the treatment of neurodegenerative diseases and substance abuse disorders.

For more information on the original study, click here.

LKT carries several compounds that modulate SK channel activity! Click the representative links below for more information.

Aryl hydrocarbon receptor as a new target for asthma

The aryl hydrocarbon receptor is a ligand-activated transcription factor that regulates biological responses to exogenous environmental toxicants such as flavonoids, polyphenols, and aromatic hydrocarbons. Activation of the aryl hydrocarbon receptor signals for changes in expression of genes involved in hematopoiesis, immune cell development, and metabolizing enzyme induction.

A recently published article in the Journal of Molecular Medicine examines the connection between the aryl hydrocarbon receptor and VEGF, a regulator of angiogenesis potentially involved in airway remodeling and other characteristics of pulmonary disease development. This study shows that synthetic aryl hydrocarbon receptor agonists increase VEGF expression, promoting tube formation in endothelial cells. Similarly, administration of environmental toxicants known to bind the aryl hydrocarbon receptor increased VEGF expression in bronchial epithelial cells of animal models.

These results indicate a role for the aryl hydrocarbon receptor in the development of airway remodeling, one physiological characteristic of asthma and other pulmonary diseases. Further research may provide a role for antagonism of the aryl hydrocarbon receptor in preventing the development of these diseases, particularly those related to environmental toxicants.

For more information on the original study, click here.

LKT carries several compounds that modulate aryl hydrocarbon receptor activity! Click the representative links below for more information.

  • L1817 Leflunomide
  • S7618 StemRegenin 1
  • S8046 R-Sulforaphane