Thursday, November 21, 2024
11/21/2024
Project Summary and Abstract Obtaining selective small molecule inhibitors is a common bottleneck in drug discovery. The challenge of selectivity is exemplified by kinase inhibitors (KIs), as high active site conservation across the kinome has hindered the development of highly selective KIs. While there are 50+ FDA approved KIs, the majority inhibit many kinases, leading to adverse events in patients and limiting their use as tool compounds. Recently, chemists have implemented ‘selectivity filters’ that engage non-conserved features of a target to obtain selectivity, however, the generality of these approaches is limited, as they rely on rare occurrences. Over the past 5 years our group has been evaluating atropisomerism as a potentially general ‘selectivity filter’. Atropisomerism is a form of chirality that arises from hindered rotation about a bond where the rotational conformers are enantiomers. Depending on the degree of hindrance to bond rotation, atropisomers can exist as stable or unstable enantiomers. Many drugs exist as unstable atropisomers yet bind their biological targets in an atropisomer- specific manner. We have shown that analogs of promiscuous compounds that are ‘locked’ into a single atropisomeric conformation possess improved target selectivity and have leveraged this to obtain highly selective inhibitors of several kinases. To understand the origin of this selectivity, we analyzed over 100 kinase/small molecule co-crystal structures and observed that the bulk of dihedral conformational space about the axis was sampled by different kinases, and that a major driver of selectivity in our previous work was the preorganization of the axis into a narrow ‘target-preferred’ conformational range. This led us to hypothesize that target selectivity can be rapidly programmed into promiscuous scaffolds via preorganization of a prospective atropisomeric axis into a specific target’s preferred dihedral conformations. We are evaluating this in the context of diverse pharmaceutically privileged scaffolds, both dependent and independent of stable atropisomerism. A second long- term goal of our research program is the development of new broadly applicable atroposelective methodologies that allow for direct access to diverse classes of pharmaceutically relevant atropisomers. Over the past 5 years our group has developed atroposelective variants of nucleophilic aromatic substitution, electrophilic aromatic substitution and vicarious nucleophilic substitution, allowing for enantioselective access to diverse atropisomeric scaffolds including biaryls, heterobiaryls, diarylethers, and diarylamines. Moving forward we plan to continue this work and extend these reactivities directly to pharmaceutical scaffolds such as those seen in AMG-510 and Bosutinib. We will also extend our atroposelective toolbox to include new reactivities such as atroposelective cyclization and radical additions.
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