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. Over expression of MCL-1 contributes to oncogenesis and confers resistance to cancer treatments. Protein-protein interactions (PPI) are constitutive of the dynamic interplay between the proand 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.