Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells.

Autor:	Rezaei Araghi R; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Bird GH; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215., Ryan JA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215., Jenson JM; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Godes M; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215., Pritz JR; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215., Grant RA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139., Letai A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215., Walensky LD; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Loren_Walensky@dfci.harvard.edu keating@mit.edu.; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215., Keating AE; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; Loren_Walensky@dfci.harvard.edu keating@mit.edu.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Jan 30; Vol. 115 (5), pp. E886-E895. Date of Electronic Publication: 2018 Jan 16.
DOI:	10.1073/pnas.1712952115
Abstrakt:	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 α-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 α-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 Å and 1.9 Å 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 workflow applicable to a host of challenging biomedical targets. Competing Interests: Conflict of interest statement: L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics.
Databáze:	MEDLINE
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