Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Apicomplexan parasites cause significant human and animal diseases.
• Calcium-dependent Protein Kinase 1 (CDPK1) is a validated drug target in these parasites.
• The glycine gatekeeper residue in CDPK1 presents a unique challenge for inhibitor design.

Purpose of the Study:

• To review recent advances in the development of Bumped Kinase Inhibitors (BKIs) targeting apicomplexan CDPK1.
• To discuss the challenges and lessons learned in preclinical candidate selection.
• To highlight the efficacy, safety, and pharmacology considerations for these potential therapeutics.

Main Methods:

• Literature review of published research on BKIs and apicomplexan parasites.
• Analysis of structure-activity relationships for CDPK1 inhibitors.
• Evaluation of preclinical data regarding efficacy, safety, and pharmacokinetic profiles.

Main Results:

• Several BKI series targeting apicomplexan CDPK1 have demonstrated potent activity.
• Understanding the glycine gatekeeper has been crucial for designing selective inhibitors.
• Preclinical studies have provided valuable insights into the pharmacological properties and potential toxicities of BKIs.

Conclusions:

• BKIs targeting CDPK1 are a promising therapeutic strategy for apicomplexan infections.
• Continued research is needed to overcome remaining challenges in efficacy, safety, and drug development.
• Lessons learned from preclinical candidate selection will guide future therapeutic development.