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.