Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Fragment-based screening identified pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2.
• Optimization efforts focused on improving CHK1 potency and selectivity while addressing synthetic tractability and chemical novelty.

Purpose of the Study:

• To demonstrate the successful progression of fragment-derived hit matter to in vivo active compounds.
• To explore fragment-growing and scaffold morphing strategies for kinase inhibitor development.

Main Methods:

• Structure-based design informed scaffold morphing strategies.
• Iterative optimization involved multiple scaffold transformations, including pyrimido[2,3-b]azaindoles, N-(pyrazin-2-yl)pyrimidin-4-amines, imidazo[4,5-c]pyridines, and isoquinolines.
• In vivo efficacy was assessed using SW620 human colon carcinoma xenografts in nude mice.

Main Results:

• A potent and highly selective isoquinoline CHK1 inhibitor, SAR-020106, was identified.
• SAR-020106 demonstrated the ability to potentiate the efficacies of irinotecan and gemcitabine in preclinical cancer models.
• The study successfully navigated challenges in potency, selectivity, synthesis, and novelty within the kinase inhibitor chemical space.

Conclusions:

• Fragment-growing and scaffold morphing, guided by structural insights, are effective strategies for advancing fragment-based leads.
• The identified isoquinoline CHK1 inhibitor represents a promising therapeutic candidate for combination cancer therapy.
• This work highlights the successful application of structure-based drug design in developing novel kinase inhibitors with in vivo activity.