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

03 May 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Drug discovery
Kinase inhibitors
RET Kinase
EGFR kinase mutants

Supplementary materials

SI Leveraging atropisomerism to obtain selective kinase inhibitors


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