Mcl-1 (myeloid cell leukemia-1) is an anti-apoptotic protein that belongs to the Bcl-2 (B-cell lymphoma 2) protein family, and is frequently overexpressed in many different human cancers. In recent years, it has been demonstrated that high levels of Mcl-1 are also associated with resistance to conventional chemotherapeutics. Thus, Mcl-1 is a promising target for the development of novel, and potentially synergistic, antineoplastics. Currently, there are no potent and selective Mcl-1 inhibitors in the literature. The surface of Mcl-1 presents a hydrophobic crevice that engages the a-helical BH3 �death� domain of pro-apoptotic proteins, such as Bak and Bim, thereby inhibiting the cell-killing functions of those proteins. By analogy with the validated approach towards the inhibition of the related anti-apoptotic protein Bcl-xL, we have developed, using molecular modeling as our guide, novel, benzodiazepine-based, low-molecular-weight compounds that mimic both faces of the pro-apoptotic BH3 a-helix as potential selective inhibitors of Mcl-1.

Towards novel, benzodiazepine-based α-helix mimetics as specific inhibitors of the Mcl-1 oncoprotein

245th National Meeting (2013)

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