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Design of rigid protein–protein interaction inhibitors enables targeting of undruggable Mcl-1

DOI: 10.1073/pnas.2221967120 DOI Help

Authors: David Hargreaves (AstraZeneca) , Rodrigo J. Carbajo (AstraZeneca) , Michael S. Bodnarchuk (AstraZeneca) , Kevin Embrey (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Martin Packer (AstraZeneca) , Sébastien L. Degorce (AstraZeneca) , Alexander W. Hird (AstraZeneca) , Jeffrey W. Johannes (AstraZeneca) , Elisabetta Chiarparin (AstraZeneca) , Markus Schade (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 120

State: Published (Approved)
Published: May 2023

Abstract: The structure-based design of small-molecule inhibitors targeting protein–protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.

Journal Keywords: AMG176; AZD5991; S64315; AMG-397; PPI inhibitor

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 20/05/2023 15:32

Discipline Tags:

Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)