Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005

Area of Science:

• Immunology
• Biochemistry
• Medicinal Chemistry

Background:

• Protein kinase C theta (PKC-θ) is crucial for T lymphocyte activation, proliferation, and cytokine release.
• PKC-θ plays a key role in T cell receptor (TCR) signaling pathways.

Purpose of the Study:

• To synthesize and characterize novel PKC-θ inhibitors.
• To establish structure-activity relationships (SAR) for optimizing inhibitor potency and drug-like properties.
• To identify a clinical candidate for T cell-mediated inflammatory diseases.

Main Methods:

• Structure-guided design and exploratory SAR studies were employed.
• Property-guided design focused on optimizing metabolic stability and cell permeability.
• In vitro kinase selectivity assays and cellular assays for IL-2 inhibition were performed.
• In vivo efficacy was evaluated in models of T cell activation.

Main Results:

• Novel PKC-θ inhibitors were synthesized with optimized C4 and C2 substitutions.
• Potent analogs with improved metabolic stability and permeability were identified.
• The lead compound CC-90005 demonstrated exquisite kinase selectivity and cellular inhibition of T cell activation.
• CC-90005 showed favorable safety profile and in vivo efficacy in acute and chronic T cell activation models.

Conclusions:

• CC-90005 is a potent and selective PKC-θ inhibitor with favorable pharmacokinetic and safety profiles.
• CC-90005 demonstrated efficacy in preclinical models, supporting its advancement.
• CC-90005 was selected for clinical development for conditions involving T cell activation.