Michigan Cancer Research Fund                                                                                            American Cancer Society
   
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Research Project Description from Daryl Staveness, PhD, 2016 MCRF Fellow

Project Name: Re-Engineering Toxic Aniline-Based Drugs with 1-Aminonorbornane Isosteres

Taking an aspirin technically qualifies as chemotherapy, but typically “chemo” tends to elicit a much more negative imagery. While there are multiple reasons a drug might have associated side effects, one rather common issue in drug development is adverse metabolism. The liver is designed to clear many foreign substances from the body, but in some cases, the liver will process active pharmaceutical ingredients into highly reactive metabolites, ultimately resulting in toxicity. This problem has stopped many promising leads from reaching approval and has even led to drugs being removed from the market.

Importantly, this reactivity (i.e. processing by liver enzymes) is necessarily tied to the chemical structure of the drug, and through decades of medicinal chemistry research, we can generally identify substructures that are at a high risk for deleterious metabolism (these are termed “structural alerts”). Anilines are one such substructure and have even been described as “the most notorious” of them all. Unfortunately, while some structural alerts can be mimicked with other motifs such that the desired pharmacology is achieved with a reduced risk of deleterious metabolism, nothing in our current chemical toolbox reliably serves as a metabolically-inert substitute for anilines. This project seeks to change that paradigm through the preparation and evaluation of 1-aminonorbornanes (aminoNBs).

Summer 2018 Update from Dr. Staveness: My work at the University of Michigan Chemistry Department focuses on harnessing the unique synthetic capabilities of visible light to enable the design of safer cancer chemotherapies. We have developed two fundamentally new photochemical transformations to prepare 1-aminonorbornanes, chemical building blocks that have not previously been explored in a pharmaceutical setting due to the lack of accessibility. With our light-driven synthetic methods, we can now evaluate the potential of 1-aminonorbornanes within drug discovery, particularly as a replacement for risk- averse building blocks such as anilines.

Anilines are commonly-used in drug development due to the ease with which they can be prepared, but they imbue the drug candidate with a high risk of metabolism-derived toxicity. Lapatinib exemplifies this issue; a frontline therapy for triple positive breast cancer, the overall clinical impact of lapatinib has been tamed by the documented risk for fatal drug-induced liver injury. This risk can be directly traced back to the presence of an aniline motif, thus re- engineering the lapatinib scaffold (or any other of the many aniline-based drugs or drug leads in oncology) to incorporate the metabolically-inert 1-aminonorbornane is anticipated to supply life-saving biological activity while avoiding the risk of this off-target toxicity.

We are in the process of synthesizing these 1-aminonorbornane-based lapatinib analogs, along with additional applications of our strategy toward hearing disorders, epilepsy, and agrochemical needs. These efforts will be reported in due course and have drawn significant interest from colleagues in the pharmaceutical industry. This intrigue paired with the sustainability and operational simplicity of our synthetic strategy is anticipated to lead to adoption of this chemistry well beyond our lapatinib re-engineering efforts, ideally contributing to a new era of safer cancer chemotherapy.

I am an MCRF fellow through 2019, at which point I will be pursuing academic positions with an intent to continue pursuing new avenues in medicinal chemistry.

November 2018 Update from Dr. Staveness: In late July, we were awarded a $1.6 million NIH R01 grant which will provide in funding over the next few years. Significantly, this award will cover the research efforts of multiple graduate students and incoming postdocs as well as support our collaborating labs to enable the downstream evaluation of our compounds.

Our first method paper is finally getting published and is online now. It is a chemistry-only paper, but provides some hints to what we're planning. We're almost done drafting the 2nd generation approach, so we'll finally be getting this work out to the rest of the drug discovery community to start using. Also, click here to read an article that the University of Michigan communications department wrote on our work.

While this does not seem immediately relevant to cancer chemotherapy, we're on the cusp of our first 1-aminonorbornane patent for the use of our aminonorbornane as agrochemical fungicides. We thought we had finally figured out what needed to be done to get to the right anticancer agents, but the aminonorbornances we were using still were not the right ones. Thanks to the help of some grad students in the lab, we did end up finding out that they had fungicidal activity. Although that was not the original intent, it does show how investing in chemistry can open up all sorts of opportunities, even beyond the original application!

Summer 2019 Update from Dr. Daryl Staveness:

As I enter the third and final year of my fellowship, I am happy to share a number of exciting updates on my project. My research is centered on employing novel visible light-mediated photochemistry to re-engineer existing or developmental cancer chemotherapies into safer, more effective drug leads. This work lies at the earliest stages of drug development, so the clinical impact will not be felt for some time. However, advances in synthetic chemistry are broadly enabling, meaning that the ultimate impact of these efforts can propagate well beyond the initial target. And that is exactly what you will see below!

In 2018, we finally began to see the first hints of translational potential of our photochemical efforts. Having spent the majority of 2017 investigating how to make the molecules of interest, we were able to provide a critical proof-of-concept early last year through the development of more metabolically-stable ion channel agonists. Our approach to designing safer drugs stems from the idea that we can replace a notoriously risk-laden building block (an aniline) with our novel, photochemically-derived system (a 1-aminonorbornane) without changing the performance in living organisms. While the aniline-based drugs are known to be processed in the liver (at times leading to severe or even fatal liver toxicity), the 1-aminonorbornanes should be inert to liver metabolism. With our ion channel agonist trial, we were able to show just that our new 1-aminonorbornane-based drug lead was entirely stable to the action of liver enzymes, yet we were still able to show activity that nearly recapitulated the parent compound. While this was intended to be only a proof-of-concept study, the observed performance was so promising that this has become the sole focus of a 4th year graduate student, and if all goes well, we will be testing these compounds in animal models of disease by the end of the year or early 2020.

A second demonstration of the broadly-enabling impact of synthetic advances comes in the form of agrochemical fungicides. While developing photochemistry to access a new class of 1-aminonorbornanes (one more amenable to the oncology applications detailed in the original proposal), we recognized that a simple modification of our compounds would make molecules bearing strong resemblance to a subset of aniline-based fungicidal agents. With the help of two graduate students, we quickly prepared a small library of new fungicidal leads and drove them up to Michigan State University, which happens to have an excellent collection of plant pathologists and extension scientists, for testing. And they worked! Not only did our novel leads prevent fungal growth, their performance was on par with modern commercial compounds. This data was promising enough to warrant a provisional patent, and if we can secure additional funding (in progress), we will be able to dedicate someone full-time to the advancement of these 1-aminonorbornane-based fungicides.

Clearly, the most relevant outcomes to the goals of MCRF are not the unexpected applications, but those directly related to the development of cancer chemotherapies. Unfortunately, we are still sitting just on the cusp of preparing our first library of cancer-specific leads, but I am confident this will be changing soon. Our target of interest is the anilinoquinazoline scaffold, a common starting point for drug discovery that has led to development of a dozen or so approved drugs and advanced clinical leads (all in oncology). Recently, we have uncovered a new route that allows us to prepare a very close relative to the anilinoquinazoline scaffold with our 1-aminonorbornane fragment incorporated. Theoretically, this leaves us just one step away from accessing the target of interest. Notably, this related scaffold has also found use in oncology, indicating that our new strategy may enable a two-pronged drug discovery effort through one unified synthetic route. This is an exciting advance; we expect to be testing out our 1-aminonorbornane anticancer leads in the coming months.

I will be doing my best to ensure that these last several months of my funding period are as productive as possible. I would like to note that the true measure of the impact of my fellowship, the totality of what we achieved on the 1-aminonorbornane project must be considered. While the re-engineered anilinoquinazolines were and are still the main focus of the work, every other discovery was directly enabled by the choice to fund my proposal back in 2016, as will all the discoveries that will be unveiled over the course of the NIH R01 grant and beyond. Given the wealth of industrial interest our 1-aminonorbornanes have drawn, the impact could become extremely broad! I hope to have more good news to share in the near future!