Kinase Inhibitors as Therapeutics: A Review

This blog was originally published in April of 2018. Today’s update includes the paper, “Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement” from Cell Chemical Biology, demonstrating the power of NanoBRET™ target engagement kinase assays in the study of kinase inhibitors.

The review “Kinase Inhibitors: the road ahead” was recently published in Nature Reviews Drug Discovery. In it, authors Fleur Ferguson and Nathanael Gray provide an up-to-date look at the “biological processes and disease areas that kinase-targeting small molecules are being developed against”. They note the related challenges and the strategies and technologies being used to efficiently generate highly-optimized kinase inhibitors.

This review describes the state of the art for kinase inhibitor therapeutics. To understand why kinase inhibitors are so important in the development of cancer (and other) therapeutics research, let’s start with the role of kinases in cellular physiology.

The road ahead for kinase inhibitor studies.

Why Kinases? Continue reading “Kinase Inhibitors as Therapeutics: A Review”

Psychedelics as Therapeutic Agents: Current Research, Potential Benefits

This past May (2019) the symposium “Psychedelic Therapy in Society: Exploring the Mechanisms of Action and Delivery of Care” was hosted by the International Forum on Consciousness at the BioPharmaceutical Technology Center in Madison, WI.

Having the good fortune to work across the street at Promega, I was able to attend this two-day conference and learn from leading researchers in psychedelics and about their use in therapy.

My interest in psychedelics is relatively new. I didn’t experiment with these substances during high school or college years. But in recent years, I’ve seen a close relative struggle with profound anxiety related to terminal disease, and another with substance abuse and depression. The lessons learned from each experience is that the battery of medicines used to treat such illness can result in additional problems for which there are currently not good medication options. And in some cases, traditional medications can cause further health problems. Continue reading “Psychedelics as Therapeutic Agents: Current Research, Potential Benefits”

B Cells, T Cells and Now X Cells?

The cause of type 1 diabetes (T1D) is not well understood. What is known is that in T1D, immune cells attack pancreatic islet cells that produce insulin. In addition, insulin is an autoantigen that activates T cells in diabetic persons.

A new discovery by Ahmed et al. could further T1D understanding. These findings are also setting B and T cell paradigms on their ear.

About B Cells and T Cells

Components of the B cell receptor.
Components of the B-cell receptor.Image by CNX OpenStax. Used with permission under Wikimedia Commons.

B cells (B lymphocytes) are part of the cellular immune response. They act by means of surface receptor molecules that are immunoglobulins. These B cell receptors are created by highly variable gene rearrangements that result in a huge variety of these surface immunoglobulin molecules. The beauty of B cell receptors (BCR) lies in the fact that, through random gene rearrangements comes a such large variety of B cell surface receptors, that any foreign antigen that makes its way into the body is recognized and snagged by a B cell receptor.

B cells then internalize, process and present these antigens to T cells. Continue reading “B Cells, T Cells and Now X Cells?”

Research-Based Training for Sustainable Use and Management of Marine Ecosystems in Namibia

In my science blog research/writing, news reports are usually pulled from US sources. But interesting scientific research is obviously being conducted in many places around the globe. When this story from Namibia came along, there was so much I didn’t know. It was time to catch up.

relief map of Namibia
Relief map of Namibia. Image by Natural Earth and Kbh3rd with permission under Wikimedia commons.

Namibia is Exactly Where in Africa?

Namibia is one of the world’s youngest countries, having gained independence from South Africa in 1990. Situated northwest of the country of South Africa on the Atlantic Ocean, Namibia is arid, composed largely of desert.

This blog is about research conducted at the Sam Nujoma Research Center, University of Namibia, on Henties Bay. Henties Bay (not shown on this map) is in the region of Erongo, located in the center of Namibia along the coast. Henties Bay has become a tourist destination in part due to the abundance of fish and marine life found there.

Sam Nujoma Research center.
The Sam Nujoma Research Center of University of Namibia, located near Henties Bay.

Continue reading “Research-Based Training for Sustainable Use and Management of Marine Ecosystems in Namibia”

Are We Doing Enough to Stop Candida Auris Infections?

Image of C. auris on plate.
The creamy colonies of C. auris look innocuous. Don’t be fooled. Photo by Shawn Lockhart – Centers for Disease Control, Public Domain, https://commons.wikimedia.org/w/index.php?curid=54680002

Life in the 21st century is full of electronic devices and apps purported to make life easier. Many of us can binge watch movies, videos and news on our phones. There are wireless headphones, electric bicycles, self-operating vacuum cleaners, wine in boxes with taps—and so much more.

This life is, however, not without challenges.

In the event that you or yours ends up in the hospital, the stay could be complicated by an unplanned, unwanted and potentially lethal infection.

No thanks to the yeast, Candida auris. Continue reading “Are We Doing Enough to Stop Candida Auris Infections?”

What’s for Dinner? Saving the Planet One Meal at a Time

On March 13, 2019, a bomb cyclone hit Denver, Colorado. With this storm the Denver area experienced a 24 millibar (mbar) drop in atmospheric pressure in a 24-hour period. At about the same time, several cities in Colorado recorded >24 mbar drops in pressure, including a 35.6mbar drop reported at Pueblo, Colorado!

The intensity of the pressure drop indicates storm severity and this storm was a record-breaker for Denver and surrounding communities.

No location on planet Earth has gone unaffected by new extremes in weather. 2018 was the hottest year on record for countries on every continent. In the past 4 months we’ve experienced record-breaking rainfall and droughts, wildfires, high temperatures and snowfall.

Food for Climate Extremes?
Climate change news is sometimes so bleak as to be overwhelming. But good scientific research and climate change-ameliorating efforts are all around us—I was encouraged to read recently that simply changing what we eat can benefit the environment. There are better food choices available to most of us, no matter what diet or cooking style we favor. Continue reading “What’s for Dinner? Saving the Planet One Meal at a Time”

Voted Drug Discovery and Development Product for 2019: NanoBRET TE Kinase Assays

Choice Drug Discovery and Development Product 2019 award
Michael Curtin, Promega, accepting the Reviewers’ Choice for Drug Discovery and Development Product of the Year award from SelectScience.

As announced at SLAS in Washington, D.C. recently, we are excited to have NanoBRET Target Engagement (TE) Intracellular Kinase Assays awarded the SelectScience Reviewers’ Choice for Drug Discovery and Development Product of the Year 2019!

The NanoBRET™ Target Engagement (TE) Kinase Assay, first available in the fall of 2017, has been getting great reviews on the SelectScience site for more than a year now. Continue reading “Voted Drug Discovery and Development Product for 2019: NanoBRET TE Kinase Assays”

A Roadmap for PROTAC Development

PROTACs or Proteolysis-Targeting Chimeras are an emerging tool in protein degradation studies, potentially suited to any need involving the removal of a specific protein. These small-molecule chimeras are exciting due to: 1) their target specificity; and 2) their ability to enable target destruction versus target inhibition.

Destruction/Inhibition: Is There a Difference?
An analogy that microbiologists (and wrestlers or anyone that has ever spent time in a locker room shower) would understand, is fungicidal versus fungistatic compounds. A fungicidal compound kills fungus. A fungistatic compound just slows the fungus down a bit.

A small-molecule inhibitor attaches to its target protein, but for how long? What inhibitor testing must be done to determine how long the inhibition lasts?

On the other hand, a small-molecule agent that causes protein degradation first targets the protein of interest, then attaches ubiquitin to that target. Once a protein is marked with ubiquitin, it’s a dead man. E3 ligase must be involved, but if the ubiquitin is added by E3, the end is near. Next stop, Hades.

This ubiquitinated protein is headed to the proteasome and proteins that go there don’t come back. Ubiquitination was called the ‘molecular kiss of death’ when this discovery was awarded the Nobel prize in Chemistry in 2004.

PROTAC components: target protein ligand, E3 ligase and linker.

About PROTACs
PROTACs are degrader molecules composed of three parts: 1) a ligand that is specific for the target protein; 2) a ligand for E3 ligase; and 3) a linker molecule that connects the two ligands. The E3 ligase is one of three enzymes that can add ubiquitin to a cellular component, but only ubiquitins added by the E3 ligase cause targeting to the proteasome (Zoppi et al.).

Continue reading “A Roadmap for PROTAC Development”
Light enters eyes and is transmitted to SCN and PHb.

Light: A Happy Pill for Dark Days?

Have you ever had a day where you feel exceptionally good? As in take on the world kind of good? You feel so much better than the previous couple of days that you stop to wonder why.

Then it dawns on you.

The sun is out. It’s been cloudy for the past week but now—SUNSHINE.

You go out to lunch or for a walk just to take in those rays. Sure, it feels warmer than your darkened office space, but it’s the light rather than warmth that’s making a difference.

You purposely don’t wear sunglasses and it feels like the light is coming in through your eyes and massaging that part of your brain that is your happy zone. Are you imagining it or is the sun really affecting how you feel?

In a study reported in the September 2018 issue of Cell we learn that this is not a figment of your or my imagination (1). There is, in fact, a type of retinal cell that transports sunlight directly to the part of our brains that affects mood.

Eyes and the Body’s Master Clock

Circadian rhythms are innate time-keeping functions found in all multicellular organisms. This subject of the 2017 Nobel prize in Physiology or Medicine, circadian rhythms are fueled by daily light-dark cycles and are critical to the function of neurologic, immune, musculoskeletal and cardiac tissues (2). Nearly every mammalian cell is affected by circadian rhythms.

The human body has a circadian master clock, the suprachiasmatic nucleus or SCN. The SCN is a highly innervated tissue located in the hypothalamus (see image). It is connected directly to the retina by the optic nerve, and thus is influenced by external light and dark.

Light enters eyes and is transmitted to SCN and PHb.
Light enters the eyes and affects the SCN (physiologic effects), and as discussed in recent research, Fernandez et al. here, the perihabenular nucleus (behavioral effects). (Image in public domain.)

The retina of the eye is the light gathering instrument for this organ. Historically, it’s been understood that the retina is composed of two cell types, rods and cones, that function in transmitting light and images to the optic nerve, which sends those signals to the brain.

Drawing of the retina with rods and cones, some nervous tissues.
Some parts of the retina. Light enters the eye (from left) and passes through to the rods and cones. Here a chemical change converts the light to nerve signals. Image based on drawing by Ramón y Cajal, 1911 and licensed under Wikimedia commons.

Studies by Hattar et al. in the early 2000s identified that another cell found in the retina, the melanopsin-containing intrinsically photoactive retinal ganglion cells (ipRGCs) as the transmitter of circadian light signals (3). Through this direct connection to the SCN, the circadian master clock, the ipRGCs can influence a wide range of light-dependent functions independent of image processing (4).

Now Fernandez et al. have identified multiple types of ipRGCs. They showed that ipRGCs that mediate the effects of light on learning work via the SCN, while the pathway for light influencing emotions is different.

They discovered a new target of ipRGC cells, the perihabenular nucleus (PHb). The PHb is a newly recognized thalamic region of the brain. The authors showed that the connection between light and mood is regulated by ipRGCs through the PHb versus the SCN. They show that the PHb is integrated into other mood-regulating centers of the thalamic region.

You can see the details of their studies here.

In Conclusion

Daylight, and lack thereof, does affect both our mood and our ability to learn. In this 2018 report, we have learned that the pathways for these effects are distinct, and gain an understanding of a new thalamic region by which the light and mood actions occur. This information could influence development of better drugs and/or therapies for major depressive disorders.

For those of us with seasonal affective disorder, the evidence is undeniable—lack of light can cause issues, from sleep-wake problems, to mood and learning issues.

And while we can’t create sunshine, a special lamp or light box may help to gain some full spectrum light. To learn more about how to choose such a lamp and when to use it, see this Mayo clinic article for details.

References

  1. Fernandez, D.C. et al. (2018) Light affects mood and learning through distinct retinal pathways. Cell 175, 71–84.
  2. Ledford, H. and Callaway, E. (2017) Circadian clock scoops Nobel prize. Nature 550, 18.
  3. Hattar, S. et al. (2002) Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–70.
  4. Hattar, S. et al. (2003) Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424(6944)76–81.

A Healthier Kind of Blues

We are in the midst of a very intense time of the year, with holidays and seasonal celebrations like Thanksgiving (recently past), Hanukkah this week and Christmas a mere two-plus weeks away.

Wrap that up with a New Year’s celebration and “Wham”—more friends, family and food/alcohol than one normally enjoys in a three-month period.

Yet it can also be the season of SAD—seasonal affective disorder, when the amount of daylight decreases daily, and for those of us in the northern latitudes, cold weather intensifies. We’re eating more, getting less sunshine and quite probably less exercise. Hibernation is great for bears, not so good for humans.

It’s the wintertime blues. For myself and many, once the solstice passes and day length starts to increase, mood improves. But noticeable day-length increases don’t really occur here until mid-February. That’s a long time to feel blue. Continue reading “A Healthier Kind of Blues”