Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology

A hallmark of Cancer is the evasion of Apoptosis. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the B-cell lymphoma-2 (Bcl-2) family of proteins that regulates the mitochondrial Apoptosis pathway. Overexpression of Mcl-1 contributes to oncogenesis and confers resistance to Cancer treatments. Protein-protein interactions (PPI) are constitutive of the dynamic interplay between the pro- and anti-apoptotic proteins of the Bcl-2 Family, which is integral to controlling the apoptotic threshold of cells. Therapeutic intervention by small molecule BH3 mimetics to pharmacologically target the PPI and antagonize Mcl-1 has made significant progress in recent years in oncology with multiple candidates entering clinical trials. This digest accounts the state-of-art Mcl-1 inhibitors with emphasis on their discovery medicinal chemistry, highlighted in structure-based drug design (SBDD) and biological evaluations.

Anti-survival/pro-apoptotic; Anticancer; BCL-2; MCL-1; MCL-1 inhibitor; Oncology; Pro-survival/anti-apoptotic; Protein-protein interactions; Structure-based drug design.