Search

Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Kivalues of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

The longest wavelength band of n-alkyl pyridinium iodides (NAPI) in solution, which is due to charge transfer processes within a contact ion pair species, serves as an empirical measure of solute-solvent interaction for a polar solute in polar solvents. An attempt has been made to correlate the energy of the transition with the chemical potential of the dipolar ion pair in a solvent. The latter quantity has been calculated using a dielectrically saturable Block-Walker reaction field model. It has been found that, for protic solvents there is a good linear correlation between the two parameters enabling the calculation of the transition energy in water. An alternative correlation involving the individual molecule dipole reaction field is also discussed. For dipolar aprotic solvents both correlations yield poorer results indicating a single parameter correlation is not sufficient. In alcoholic binary systems the solute-solvent interaction is a linear function of the bulk reaction fields of the component solvents. But in the case of aprotic-alcoholic solvents, where specificities of interaction differ, the solute sees an environment the composition of which differs from that of the bulk.