Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Phosphoinositide 3-kinases (PI3Ks) are critical lipid kinases regulating cell proliferation, migration, and differentiation.
• Dysregulation of the PI3K pathway, particularly PI3Kα, is common in various cancers due to overexpression, amplification, mutations, or PTEN loss.
• PI3K inhibitors are a promising therapeutic strategy for cancer treatment.

Purpose of the Study:

• To rapidly improve the potency of a benzothiazole fragment hit against PI3 kinases.
• To optimize the initial chemotype through scaffold hopping to identify novel PI3K inhibitors.
• To discover compounds with potent in vitro activity against all class I PI3Ks and favorable pharmacokinetic profiles.

Main Methods:

• Structure-based drug design was employed to enhance the potency of the initial benzothiazole fragment.
• Scaffold hopping strategies were utilized to explore novel chemical space and optimize lead compounds.
• In vitro assays were performed to evaluate the activity against all class I PI3 kinases.
• Pharmacokinetic properties of the identified compounds were assessed.

Main Results:

• The potency of the benzothiazole fragment was significantly improved using structural insights.
• Scaffold hopping led to the identification of a novel series of 2-acetamido-5-heteroaryl imidazopyridines.
• These compounds demonstrated potent in vitro activity against all class I PI3 kinases.
• The optimized compounds exhibited attractive pharmacokinetic properties.

Conclusions:

• A novel series of 2-acetamido-5-heteroaryl imidazopyridines were identified as potent PI3K inhibitors.
• The optimization strategy, involving structure-based design and scaffold hopping, was successful.
• These compounds represent promising drug candidates for cancer therapy targeting the PI3K pathway.