Iterative optimization yields Mcl-1–targeting stapled peptides with selective cytotoxicity to Mcl-1–dependent cancer cells
- 16 January 2018
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 115 (5), E886-E895
- https://doi.org/10.1073/pnas.1712952115
Abstract
Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1-binding peptides into alpha-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1-dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or "staple" that stabilizes alpha-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 angstrom and 1.9 angstrom resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. This work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation work-flow applicable to a host of challenging biomedical targets.Keywords
This publication has 63 references indexed in Scilit:
- Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1Blood, 2016
- Mitochondria—Judges and Executioners of Cell Death SentencesMolecular Cell, 2016
- Attacking cancer's Achilles heel: antagonism of anti‐apoptotic BCL‐2 family membersThe FEBS Journal, 2015
- Myeloid cell leukemia-1 is an important apoptotic survival factor in triple-negative breast cancerCell Death & Differentiation, 2015
- Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53Genes & Development, 2014
- Control of apoptosis by the BCL-2 protein family: implications for physiology and therapyNature Reviews Molecular Cell Biology, 2013
- Chemical Genomics Identifies Small-Molecule MCL1 Repressors and BCL-xL as a Predictor of MCL1 DependencyCancer Cell, 2012
- Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemiaGenes & Development, 2012
- Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemiaCancer Cell, 2006
- Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family membersCancer Cell, 2006