Exploring Atropisomerism in Drug Discovery

Jeffrey Gustafson's (San Diego State University, 2015 & 2017 New Investigator, 2018 CSU I-Corps Summer Sprint) medicinal chemistry group synthesizes atropisomers, or small molecules that have locked or hindered rotation around a single bond. He explains, "I am fascinated by this problem because there are many angles to it that span chemistry, biochemistry and cell biology…atropisomerism was an academic curiosity that was really under-explored when I was a graduate student. My Ph.D. work represented one of the earliest examples of a catalytic enantioselective route towards atropisomers. Then I did my postdoctoral work in a Molecular, Cellular, and Developmental Biology department as a medicinal chemist (which in academia we call a chemical biologist). This experience led me to several revelations, notably that atropisomerism was pervasive in drug discovery, and that small molecules were not nearly as selective as advertised."

Gustafson brought his interdisciplinary perspective to SDSU and in 2015 published a paper on atropisomeric kinase inhibitors in Angewandte Chemie. Their work pointed the way to a surprisingly simple strategy to increase the target selectivity of kinase inhibitors. Gustafson explains, "To be honest, at the time I did not think the results were ready for primetime, however, I presented this work at a Gordon Research Conference and got enthusiastic feedback from some fantastic scientists which led me to submit it to a high-end journal. What really surprised me, was when it came out, several leading journals including ACS Chemical Biology highlighted it. The Medicinal Chemistry division of ACS asked me to speak in a session on atropisomerism in drug discovery during the spring 2018 National Meeting. This allowed our work to be introduced to a large audience (mostly industrial medicinal chemists), and eventually led to a nice article in C&E News."

During the same period Gustafson was unsuccessful winning grant funding from the NSF and NIH, so turned to CSUPERB New Investigator grant program to get his lab in San Diego up and running. He explains, "The support from CSUPERB has been critical to my lab's success…During my fourth year at SDSU, I kept my lab running and obtained key preliminary results thanks to gritty students and funding from CSUPERB's New Investigator grant. Notably, we were able to get several in-house kinase inhibitor assays up and running, which allowed us to get exciting preliminary results for an NIH proposal that was funded." The two students funded by CSUPERB used their training in the Gustafson lab in interesting ways: one moved on to doctoral studies at University of Colorado Boulder and the other co-founded a chemical analysis company.

Now the group has funding from both NIH and NSF. He says, "The biggest way things have changed is I have been able to [hire] students and bring in two excellent postdocs (one of my postdocs is looking for PUI positions and is very intrigued by the prospect of staying in the CSU system). I have also been able to send my students to conferences important for their academic development…Funding from the NSF and NIH has also helped us expand our biological programs faster than I could have imagined."

With the extra bandwidth, the Gustafson lab decided to try out CSU I-Corps this summer. As a result, his "students caught the start-up bug, and they are actively (with my blessing) planning to start a company based on our research. For me, the most striking part was growing my professional network in San Diego. I've spoken with so many people throughout the biotech and medicinal chemistry communities, and these conversations really put things in perspective. I-Corps also taught me how to be a better listener and to better assess the problems of others."

Gustafson came to SDSU from Yale University. He says, "SDSU operates by a teacher-scholar model. I find the teaching part makes me a better scientist and communicator and can be a lot of fun. I also appreciate the commitment to undergraduate research at SDSU (and the CSU system, in general). I feel I am making a huge difference in the lives of undergraduates who do research in my lab, and I get very excited when they have a major triumph."

"While on my tenure tour last year I came to the realization that at SDSU, and the CSU in general, we are doing science on a level comparable to that of 'top' schools…Furthermore, I strongly believe that the CSU is the best place in the world for undergraduate research. I think this is illustrated nicely by the quality of student posters presented each year at [the Annual CSU Biotechnology Symposium]. As research faculty in the CSU we should be proud of this and own our CSU credentials, because not only are we teaching classes and doing excellent research, but we are doing it as we are shaping the lives of young students who largely come from backgrounds that are disadvantaged compared to their peers at the 'top' schools."

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