These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
2 files

Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities Towards EGFR Mutants

submitted on 01.05.2019, 18:46 and posted on 03.05.2019, 15:47 by Sean T. Toenjes, Valeria Garcia, Sean M. Maddox, Greg A. Dawson, Maria A. Ortiz, F. Javier Piedrafita, Jeffrey Gustafson

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis, however most small-molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target RET kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug resistant EGFR mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.


MIRA: Atropisomerism as a means to increase target selectivity and as inspiration for new chemistry

National Institute of General Medical Sciences

Find out more...


Email Address of Submitting Author


San Diego State University


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

S.T.T., S. M. M. and J.L.G are inventors on a patent application PCT/US18/38737 submitted by San Diego State University that covers compounds, compisitions and methods for the RET and EGFR mutant inhibitors in this paper for the treatment of diseases and disorders.