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/>Studies from our lab showed that target selectivity could be increased by narrowing of the accessible dihedral conformations about the atropisomeric axis. As a case study, we first evaluated a commonly used pyrrolopyrmidine inhibitor scaffold’s different energy conformation as we rotated its atropoisomeric dihedral axis.  This showed the lowest energy conformations of this scaffold were located towards a more orthogonal state, with inhibitors containing bulkier ortho substituents possessing narrower (less flexible) low-energy conformational windows.  Next, we performed an analysis of PDB ligands where we measured the dihedral angles of co-crystalized pyrrolopyrimidine ligands bound to various kinases.   While many different conformations bound different kinases, there were a few kinases (RET and mutant EGFR) that preferred their ligands to be orientated more towards orthogonality.  We then synthesized atropisomeric inhibitors possessing narrow orthogonal-like conformations and found multiple analogs were potent towards RET and mutant EGFR and also did not possess activity toward kinases that preferred conformations outside the inhibitors' conformational window.<br/>

Conformational analysis of atropisomerism in privileged scaffolds in medicinal chemistry

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.