Aberrant kinase activity is involved in many different diseases, leading to the development of over 40 FDA approved kinase inhibitors.  Due to a high degree of kinase active site conservation, most kinase inhibitors possess activities towards several kinases causing off-target side effects limiting the safety and efficacy of a potential therapeutic and its usefulness as a chemical probe.  81% of FDA approved kinase inhibitors contain at least one rotational axis between two aromatic rings. This leads to an extended form of chirality called atropisomerism, where the two different rotational conformers can either exist as a rapidly racemizing mixture or isolable enantiomers. Most bioactives, as designed, exist as a rapidly interconverting atropisomeric mixture, however, when they bind to their target active site, they tend to do so in an atropisomeric fashion. The presence of the non-relevant atropisomer via interconversion or stable racemic mixture can result in off-target inhibition.<br/><br/>We have leveraged atropisomerism as a design element to rapidly obtain simple, selective potent inhibitors of RET kinase, whose aberrant activation is found in subsets of breast, lung and thyroid cancers.  We hypothesize that the basis of the improved selectivity is the narrowing of the accessible dihedral conformations about the atropisomeric axis. To test this hypothesis, we evaluated the lead inhibitors against EGFR mutants which bind ligands with comparable dihedral angles to RET, discovering a potent inhibitor of the vaunted triple mutant L858R T790M C797S EGFR. Importantly the (Ra)-atropisomer displayed potent cellular activities in RET and mutant EGFR driven cellular models of cancer. As more compounds are tested, we will iteratively optimize towards RET and EGFR T790M, potentially leading to valuable chemical probes and/or novel therapeutics.<br/>

Leveraging atropisomerism to obtain a selective inhibitor of RET kinase with secondary activities towards EGFR mutants

2019 Fall National Meeting

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