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

ABSTRACT: 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 rearranged during transfection (RET) kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformat

SUBMITTER: Toenjes ST 

PROVIDER: S-EPMC7259470 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature