Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for...

Area of Science:

• Oncology
• Pharmacology
• Drug Discovery

Background:

• Checkpoint inhibitors have shown significant success in cancer treatment.
• Combining indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors with PD-1/PD-L1 antibodies is a strategy to enhance cancer response rates.
• Extensive glucuronidation of hydroxyamidine-based IDO1 inhibitors in humans presents a challenge.

Purpose of the Study:

• To design and optimize novel IDO1 inhibitors addressing the glucuronidation shortcomings of existing hydroxyamidine compounds.
• To evaluate the biochemical and cellular activity, in vitro ADME/PK profile, and in vivo efficacy of optimized IDO1 inhibitors.

Main Methods:

• Utilized the hydroxyamidine pharmacophore of INCB14943 as a starting point for new inhibitor design.
• Employed a stability assay with recombinant UGT1A9 enzyme and human hepatocytes to measure glucuronide formation.
• Assessed cellular and biochemical IDO1 inhibition (IC50), in vitro ADME/PK properties, and in vivo efficacy in a cancer animal model.

Main Results:

• Optimized analog 24 achieved low nanomolar IDO1 IC50 values, indicating potent inhibition.
• Compound 24 exhibited a suitable in vitro ADME/PK profile and demonstrated efficacy in a preclinical cancer model.
• In a humanized liver mouse model, compound 24 showed significantly reduced glucuronidation compared to epacadostat (2).

Conclusions:

• Novel IDO1 inhibitors were successfully developed, overcoming the glucuronidation liabilities of previous hydroxyamidine-based compounds.
• Optimized analog 24 represents a promising drug candidate with potent IDO1 inhibition, favorable pharmacokinetics, and reduced glucuronidation.
• These findings support the potential of compound 24 as a component of combination cancer immunotherapies.