Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors
In this article from the Institute for Cancer Research, binders of B-cell lymphoma 6 protein were sought. Previous work showed that there was potential hydrophobic pocket adjacent to the lead series and careful work to fill this pocket was pursued. Initial approaches considered fused rings; experimentation with ring size and changes of hybridisation at various points in the ring led to a 7-membered ring containing NH and O groups.
Some variations of small alkyl groups around the ring then completed the optimisation of the shape complementarity of the compounds to the hydrophobic pocket. The effect of getting the shape of the molecule “right” was illustrated by showing how the addition of hydrophobic groups that don’t give a molecule of the required shape simply lead to an increase in logD but not in LLE whereas those that tune the shape to the pocket see the LLE go up. It is unusual to see shape so clearly used as an optimisation parameter; having three-dimensional structures certainly helps to facilitate such an approach but there are computational tools that can help navigate the shape space of molecules even without the protein structure being available.
Bellenie, Hoelder et al J. Med. Chem.2022 Published 3rd June 2022 http://doi.org/10.1021/acs.jmedchem.1c02174