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

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.

 

Comments:

The passage you provided discusses the challenges associated with designing small-molecule inhibitors that target protein-protein interactions (PPIs). Specifically, the focus is on myeloid cell leukemia 1 (Mcl-1), a protein involved in hematological cancer, and its potential as a target for therapy.

Traditionally, designing inhibitors for PPIs has been difficult because the protein binding sites are often wide and shallow. However, despite previous beliefs that Mcl-1 was "undruggable," seven small-molecule inhibitors targeting Mcl-1 have recently entered clinical trials.

The passage highlights the crystal structure of one of these clinical-stage inhibitors, called AMG-176, bound to Mcl-1. The researchers also analyze the interaction of AMG-176 with two other clinical inhibitors, namely AZD5991 and S64315. Through X-ray data, the researchers observed that Mcl-1 exhibits high flexibility and that the binding of these inhibitors induces a deepening of the protein's binding pocket.

Additionally, the researchers employed Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis to investigate the inhibitors further. They found that the unique induced fit observed in Mcl-1 is achieved by designing highly rigid inhibitors that are preorganized in their bioactive conformation.

Overall, this work provides valuable insights into the design principles for targeting PPIs more effectively. By elucidating the key chemistry involved in the interaction between inhibitors and Mcl-1, the study presents a roadmap for developing therapies that target PPIs, which have been relatively unexplored until now.

Related Products

Cat.No. Product Name Information
S8836 MIK665 (S64315) MIK665 (S64315) is an inhibitor of induced myeloid leukemia cell differentiation protein Mcl-1 with Ki value of 1.2 nM and has potential pro-apoptotic and antineoplastic activities.

Related Targets

Bcl-2