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Protease Stability Correlates with Efficacy for High-Affinity, Cell Penetrant MDM2-Binding Stapled Peptides

27 Pages Posted: 26 May 2020 Sneak Peek Status: Under Review

See all articles by Lydia Atangcho

Lydia Atangcho

University of Michigan at Ann Arbor - Department of Chemical Engineering

Tejas Navaratna

University of Michigan at Ann Arbor - Department of Chemical Engineering

Mukesh Mahajan

Harvard University - Dana-Farber Cancer Institute

Marshall Case

University of Michigan at Ann Arbor - Department of Chemical Engineering

Kirsten Deprey

Tufts University - Department of Chemistry

Hannah Levy

University of Michigan at Ann Arbor - Department of Molecular, Cellular, and Developmental Biology

Rahul Gopinath

University of Michigan at Ann Arbor - Department of Chemical Engineering

Greg Gueorguiev

University of Michigan at Ann Arbor - Department of Chemical Engineering

Joshua Kritzer

Tufts University - Department of Chemistry

Greg Thurber

University of Michigan at Ann Arbor - Department of Chemical Engineering

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Abstract

Nearly two-thirds of all disease-associated proteins are ‘undruggable’ by modern therapeutics, meaning they are inside cells, out of the reach of biologics, but lack small molecule binding pockets. Stabilized peptides have the potential to hit these targets. However, the design criteria for developing agents that can reach and disrupt their target are poorly understood. This work focuses on the physicochemical properties of three newly-developed high affinity double-click stabilized MDM2/p53 inhibiting peptides that have favorable in vitro characteristics including protease stability, cytosolic access, and target-specific cell killing. These properties are distinct fromATSP-7041, the only p53-based peptide that has led to a clinical lead compound. We highlight a promising peptide variant with an added disulfide-bond backbone modification that demonstrates sub-micromolar cell killing in the presence of serum, comparable to the published in vitro potency of ATSP-7041. Overall, these peptides help better define the landscape needed for effective intracellular biologics.

Keywords: double-click stabilization, cytosolic penetration, protease stability, lipophilicity, alpha helixpeptides, p53 inhibition, cancer therapeutics

Suggested Citation

Atangcho, Lydia and Navaratna, Tejas and Mahajan, Mukesh and Case, Marshall and Deprey, Kirsten and Levy, Hannah and Gopinath, Rahul and Gueorguiev, Greg and Kritzer, Joshua and Thurber, Greg, Protease Stability Correlates with Efficacy for High-Affinity, Cell Penetrant MDM2-Binding Stapled Peptides. Available at SSRN: https://ssrn.com/abstract=3596598 or http://dx.doi.org/10.2139/ssrn.3596598
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Lydia Atangcho

University of Michigan at Ann Arbor - Department of Chemical Engineering

Tejas Navaratna

University of Michigan at Ann Arbor - Department of Chemical Engineering

Mukesh Mahajan

Harvard University - Dana-Farber Cancer Institute

450 Brookline Avenue
Boston, MA 02215
United States

Marshall Case

University of Michigan at Ann Arbor - Department of Chemical Engineering

Kirsten Deprey

Tufts University - Department of Chemistry

Medford, MA 02155
United States

Hannah Levy

University of Michigan at Ann Arbor - Department of Molecular, Cellular, and Developmental Biology

Rahul Gopinath

University of Michigan at Ann Arbor - Department of Chemical Engineering

United States

Greg Gueorguiev

University of Michigan at Ann Arbor - Department of Chemical Engineering

Joshua Kritzer

Tufts University - Department of Chemistry

Medford, MA 02155
United States

Greg Thurber (Contact Author)

University of Michigan at Ann Arbor - Department of Chemical Engineering ( email )

United States

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