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In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-x L /Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-x L .

Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant ovarian cancers. To correct the unfavorable intrinsic physico-chemical properties of this BCS II drug, a formulation strategy was implied in the drug discovery step. Pyridoclax-loaded nanoemulsions (NEs) were developed to permit its preclinical evaluation. The resulting nanoemulsions displayed a mean size of about 100 nm and a high encapsulation efficiency (>95%) at a drug loading of 2 wt%, enabling a 1,000-fold increase of the Pyridoclax apparent solubility. NEs have enabled a sustained release of the drug as assayed by a dialysis bag method. In addition, anti-tumor effects of the Pyridoclax-loaded nanoemulsions (PNEs) showed a 2.5-fold higher activity on chemoresistant ovarian cancer cells than free Pyridoclax. This effect was confirmed by a drastic increase of caspase 3/7 activation from 10 µM PNEs, as newly objectified by real time apoptose imaging. The Pyridoclax bioavailability was kept unchanged after encapsulation in nanoemulsions as determined in a mice model after oral administration. Thus, NEs should permit valuable Pyridoclax oral administration, and valorization of this promising anticancer drug by maintaining its original anticancer activity, and by reducing the Pyridoclax therapeutic concentration. [ABSTRACT FROM AUTHOR]