Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 120, Issue 21, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2221967120
Keywords
AMG176; AZD5991; S64315; AMG-397; PPI inhibitor
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Researchers report the crystal structure of Mcl-1 and its interactions with clinical inhibitors AMG-176, AZD5991 and S64315. They found that highly rigid inhibitors, preorganized in their bioactive conformation, can induce pocket deepening. This work provides a roadmap for targeting the largely untapped PPI class more successfully.
The structure-based design of small-molecule inhibitors targeting protein-protein inter-actions (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 remarka-ble 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 conforma-tion. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.
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