Preferential targeting of MCL-1 by a hydrocarbon-stapled BIM BH3 peptide

Abstract

// Abbas Hadji 1 , Greta K. Schmitt 1 , Mathew R. Schnorenberg 1 , 2 , Lauren Roach 1 , Connie M. Hickey 1 , Logan B. Leak 1 , Matthew V. Tirrell 2 and James L. LaBelle 1 1 Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation and Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA 2 Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA Correspondence to: James L. LaBelle, email: jlabelle@peds.bsd.uchicago.edu Keywords: MCL-1; BIM; BH3 mimetic; stapled peptides; apoptosis Received: February 08, 2019     Accepted: October 04, 2019     Published: October 22, 2019 ABSTRACT BCL-2 family proteins are central regulators of apoptosis and represent prime therapeutic targets for overcoming cell death resistance in malignancies. However, plasticity of anti-apoptotic members, such as MCL-1, often allows for a switch in cell death dependency patterns that lie outside the binding profile of targeted BH3-mimetics. Therefore discovery of therapeutics that effectively inactivate all anti-apoptotic members is a high priority. To address this we tested the potency of a hydrocarbon stapled BIM BH3 peptide (BIM SAHB A ) to overcome both BCL-2 and MCL-1 apoptotic resistance given BIM’s naturally wide ranging affinity for all BCL-2 family multidomain members. BIM SAHB A effectively killed diffuse large B-cell lymphoma (DLBCL) cell lines regardless of their anti-apoptotic dependence. Despite BIM BH3’s ability to bind all BCL-2 anti-apoptotic proteins, BIM SAHB A ’s dominant intracellular target was MCL-1 and this specificity was exploited in sequenced combination BH3-mimetic treatments targeting BCL-2, BCL-X L , and BCL-W. Extending this MCL-1 functional dependence, mouse embryonic fibroblasts (MEFs) deficient in MCL-1 were resistant to mitochondrial changes induced by BIM SAHB A . This study demonstrates the importance of understanding BH3 mimetic functional intracellular affinities for optimized use and highlights the diagnostic and therapeutic promise of a BIM BH3 peptide mimetic as a potential MCL-1 inhibitor.