Category: drug discovery

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Breakthrough advances in 2018 so far: flu, germs, and cancer

2018 medicine breakthrough review!

So far this year has seen some pretty important research breakthrough advances in several key areas of health and medicine.  I want to briefly describe some of what we’ve seen in just the first few months of 2018.

Flu

A pharmaceutical company in Japan has released phase 3 trial results showing that its drug, Xofluza, can effectively kill the virus in just 24 hours in infected humans.  And it can do this with just one single dose, compared to a 10-dose, three day regimen of Tamiflu. The drug works by inhibiting an endonuclease needed for replication of the virus.

Germs

It is common knowledge that antibiotics are over-prescribed and over-used.  This fact has led to the rise of MRSA and other resistant bacteria which threaten human health.  Although it is thought that bacteria could be a source of novel antibiotics since they are in constant chemical warfare with each other, most bacteria aren’t culture-friendly in the lab and so researchers haven’t been looking at them for leads.  Until now.

Malacidin drugs kill multi-drug resistant S. Aureus in tests on rats.

By adopting whole genome sequencing approaches to soil bacterial diversity, researchers were able to screen for gene clusters associated with calcium-binding motifs known for antibiotic activity.   The result was the discovery of a novel class of lipo-peptides, called malacidins A and B.  They showed potent activity against MRSA in skin infection models in rats.

The researchers estimate that 99% of bacterial natural-product antibiotic compounds remain unexplored at present.

Cancer

2017 and 2018 have seen some major advances with cancer treatment.   It seems that the field is moving away from the focus on small-molecule drugs towards harnessing the patient’s own immune system to attack cancer.  The CAR-T therapies for pediatric leukemia appear extremely promising.  These kinds of therapies are now in trials for a wide range of blood and solid tumors.

A great summary of the advances being made is available here from the Fred Hutchinson Cancer Research Center.   Here is how Dr. Gilliland, President of Fred Hutch, begins his review of the advances:

I’ve gone on record to say that by 2025, cancer researchers will have developed curative therapeutic approaches for most if not all cancers.

I took some flak for putting that stake in the ground. But we in the cancer research field are making incredible strides toward better and safer, potentially curative treatments for cancer, and I’m excited for what’s next. I believe that we must set a high bar, execute and implement — that there should be no excuses for not advancing the field at that pace.

This is a stunning statement on its own;  but made even more so because it is usually the scientists in the day-to-day trenches of research who are themselves the most pessimistic about the possibility of rapid advances.

Additionally, an important paper came out recently proposing a novel paradigm for understanding and modeling cancer incidence with age.  For a long time the dominant model has been the “two-hit” hypothesis which predicts that clinically-observable cancers arise when a cell acquires sufficient mutations in tumor-suppressor genes to become a tumor.

This paper challenges that notion and shows that a model of thymic function decline (the thymus produces T-cells) over time better describes the incidence of cancers with age.   This model better fits the data and leads to the conclusion that cancers are continually arising in our bodies, but it is our properly functioning immune system that roots them out and prevents clinical disease from emerging.  This model also helps explain why novel cancer immunotherapies are so potent and why focus has shifted to supporting and activating T-cells.

Declining T cell production leads to increasing disease incidence with age.

 

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Is CB-5083 a promising new weapon against multiple myeloma?

Why care about p97?

In my postdoc work, I participated in a large team effort at designing a small molecule inhibitor of the p97 AAA-ATPase.

A crystal structure of the p97 ATPase.  The D2 domain is shown in dark blue.

The funding for this project came from the National Cancer Institute (NCI) and was premised on the idea that inhibiting p97 in certain types of cancer cells that depend heavily on the endoplasmic-reticulum associated degradation pathway (ERAD) would have the effect of triggering the unfolded-protein response and apoptosis pathways within the rapidly growing tumor cell populations.   This is because p97 is a critical regulator and component of ERAD, and when it is inhibited, the cell experiences unbalanced protein homeostasis and unfolded protein stress.

Drug design is an extremely challenging problem, and even with a large group of researchers it took us several years to find a compound that showed promising inhibition against p97.   Our results were published in ACS Med Chem Letters in 2016.   The compound we discovered, indole amide 3, has high solubility, permeability, and stability.  It binds an allosteric site on the D2 domain  with sub-micromolar affinity.   Unfortunately, it just didn’t have enough binding affinity to be active in vivo.

A different approach yields new promise

At around the same time we were developing our allosteric inhibitor series, another group was developing an ATP competitive D2 domain inhibitor of p97, called CB-5083.  In contrast to our compound, this one binds directly to the D2 ATP enzyme site with nanomolar affinity.

CB-5083.

The compound also demonstrated potent and specific p97 inhibition activity in mouse xenograft models of tumors.

An advance in myeloma cancer therapy

A more recent paper (Nov 2017) shows activity for CB-5083 against multiple myeloma (MM) cell lines and in vivo MM models.  From the abstract:

CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents.

Standard of care agents, like bortezomib, are proteasome inhibitors (PI).  Using a PI results in broad inhibition of the proteasome system across many cell types, not just tumor cells, and thus a high likelihood of side effects.  p97 is upstream of the proteasome and targeting it is more narrow in scope, because MM cells rely so heavily on the protein homeostasis activities of the ERAD pathway.

Hope for Phase 1 success

CB-5083 was also found to enhance the activity of bortezomib both in vitro and in vivo and also was active in bortezomib-resistance models of MM.  This paves the way for a potential combination therapy or another line of therapy if resistance develops as a result of earlier treatment with PIs.   Clinical trials are now ongoing in Phase 1 for patients who have exhausted other medications.  Hopefully CB-5083 makes it to the market soon, if trials prove it to be safe and efficacious, so that oncologists and patients have another weapon in the fight against MM.

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Why is low-dose naltrexone beneficial for many diverse diseases?

Recently, I’ve been doing some research into Hailey-Hailey Disease (HHD).  HHD is an autosomal dominant genetic disorder that leads to severe dermatosis.  The disease causing variants are located in the ATP2C1 gene, which is a magnesium-dependent, calcium transporting ATPase.

There are unfortunately few treatment options for HHD.  Many treatment options have been tried, from corticosteroids to tacrolimus.   There are very few HHD patients, and therefore no large scale clinical trials of therapies for this disease.

I came across a paper that shows that a novel approach, low-dose naltrexone (LDN), may be an effective and low-cost therapy for treating HHD.  What is more remarkable, however, is the fact that LDN has already been used with success to treat many diseases like fibromyalgia, Crohn’s disease, and HIV. 

Here is the complete list of diseases that LDN has been used to treat with some success according to some case reports and small-scale clinical trials:

Atopic eczema

Cholestatic pruritus

Crohn’s Disease

Adenoid cystic tongue carcinoma

Fibromyalgia

HIV

Multiple Sclerosis

Chronic eczema and pruritis

Hailey-Hailey Disease

******

How is LDN effective across so many seemingly unrelated diseases?  I can’t really answer that question.  We do know that naltrexone is an opioid receptor inhibitor that is used in the treatment of alcohol and opioid abuse at higher doses.  At low dose, the mechanism of action is less clear, but some studies suggest increases in beta endorphins and suppression of cytokines using LDN.

As of now, LDN remains an “off-label” use of naltrexone and in the realm of internet anecdotes until more rigorous studies can be completed.  Regardless, it is an exciting development in the potential treatment of rare diseases, like HHD.

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Practical Fragments blog has reviewed our paper!

Our latest fragment-based drug discovery paper against the p97 ATPase has been noticed and reviewed favorably by the widely-read Practical Fragments blog.

Here is an excerpt from that review:

“The protein p97 is important in regulating protein homeostasis, and thus a potential anti-cancer target. But this is no low-hanging fruit: the protein has three domains and assembles into a hexamer. Two domains, D1 and D2, are ATPases. The third (N) domain binds to other proteins in the cell. All the domains are dynamic and interdependent. Oh, and crystallography is tough. Previous efforts have identified inhibitors of the D2 domain, but not the others. Not to be put off by difficult challenges, a group of researchers at the University of California San Francisco (UCSF) led by Michelle Arkin and Mark Kelly have performed fragment screening against the D1 and N domains, and report their adventures in J. Biomol. Screen.

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Cancer immunotherapy and the role of tryptophan

 

cancer immunotherapy drug 1-MT
DL-1-Methyltryptophan

 

Background

In the body, L-tryptophan is catabolized by an enzyme called Indoleamine 2,3-dioxygenase (IDO) to form a class of molecules known as kynurenines.  These compounds have been shown to be immunosuppresive, preventing inflammation and T-cell mobilization.  Additionally, depletion of cellular stores of L-tryptophan also appears to induce down-regulation of the  immune response.

What does this have to do with cancer immunotherapy?  Interestingly, cancer actively hijacks the IDO pathway to promote immune system suppression and tolerance to tumor cell antigens by overexpressing IDO in the tumor, at host cells in the immediate area of the tumor, and at tumor-draining lymph nodes where T-cells could normally become activated against tumor antigens.

Think of it like a beekeeper using smoke to keep the bees calm as the keeper removes honey from the hive.   By upregulating the expression and activity of the IDO pathway, tumors effectively “hide” from the immune system while they grow out of control in the host tissue.  But this exploitation of the body’s own immune regulation by cancer also presents a weakness that can leveraged in the fight against tumor progression.

Inhibiting IDO to enable tumor recognition

Enter 1-methyl-DL-tryptophan (1MT), pictured above.  1MT is known to be an inhibitor of IDO that works presumably by mimicking the natural substrate (although I believe this has not been shown explicitly).   IDO inhibition by 1MT has been shown to work in combination with chemotherapy approaches to limit tumor progression in mouse models.

Adding 1MT to chemotherapy treatments allows the host immune system to mediate a response to the tumor cells, especially in the presence of dying tumor cells undergoing apoptosis and releasing antigen.  By taking away tumor-induced immune tolerance, 1MT inhibition of IDO allows the T-cell system to recognize, attack and destroy cancer cells in synergy with chemotherapy.

Early  clinical trials involving 1MT appear to be ongoing, with work being done by NewLink Genetics in Ames, IA.

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References

Munn, DH.  Indoleamine 2,3 Dioxygenase and Tumor-Induced Immune Suppresion.  Ch. 17 Innate Immune Regulation and Cancer Immunotherapy.      DOI: 10.1007/978-1-4419-9914-6_17, Springer Science

Wainright, et al.  Clinincal Cancer Research October 15, 2014 20:5290–5301

https://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase