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

Araghi, Raheleh Rezaei; Bird, Gregory H.; Ryan, Jeremy A.; Jenson, Justin M.; Godes, Marina; Pritz, Jonathan R.; Grant, Robert A.; Letai, Anthony; Walensky, Loren D.; Keating, Amy E.

doi:10.1073/pnas.1712952115

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

Journal Article · Tue Jan 16 00:00:00 EST 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1712952115· OSTI ID:1424793

Araghi, Raheleh Rezaei ^[1]; Bird, Gregory H. ^[2]; Ryan, Jeremy A. ^[2]; Jenson, Justin M. ^[1]; Godes, Marina ^[2]; Pritz, Jonathan R. ^[2]; Grant, Robert A. ^[1]; Letai, Anthony ^[2]; Walensky, Loren D. ^[2]; Keating, Amy E. ^[1]

Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Dana-Farber Cancer Inst., Boston, MA (United States)

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. Here, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; R35 CA197583; R01 GM110048; R50 CA211399

OSTI ID:: 1424793

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 5; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 45 works

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59 BASIC BIOLOGICAL SCIENCES
stapled peptide
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apoptosis
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inhibitor

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

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