Disruption of MCL1/BOK transmembrane interaction as a novel strategy to induce cell death in tumours.

MCL1, an anti-apoptotic BCL-2 family member, is frequently overexpressed in multiple tumour types and correlates with poor prognosis; however, targeting its cytosolic domain to release pro-apoptotic effectors has been limited by cardiotoxicity in clinical trials. In this study, we describe a chemically mediated disruption of the MCL1/BOK transmembrane interaction that induces tumour cell death without affecting viability in 3D cardiomyocyte cultures. Molecular dynamics simulations and LUV-based assays converged to show that the MBoIN179 disrupts transmembrane dimerization, thereby restoring BOK pore formation inhibited by MCL1. In cells, interference with the MCL1/BOK transmembrane interaction promoted relocalization of BOK from the endoplasmic reticulum to mitochondria, where it engaged a BOK-dependent cell death program in both 2D and 3D breast cancer models, leading to reduced tumour growth and metastasis in vivo. Analysis of patient tumour microarrays further showed that BOK is overexpressed in aggressive breast cancer subtypes and correlates with poor prognosis. Together, these findings identify the MCL1/BOK transmembrane interaction as a tumour-selective vulnerability that can be engaged to promote antitumour responses with cardiac safety, highlighting transmembrane interactions as viable molecular targets.