Natural Product-like Fragments Unlock Novel Chemotypes for a Kinase Target─Exploring Options beyond the Flatland

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Protein kinase A (PKA) is a crucial enzyme in cellular signaling.
• Developing selective kinase inhibitors is a significant challenge in drug discovery.
• Novel chemical scaffolds are needed to overcome limitations of existing kinase inhibitors.

Purpose of the Study:

• To perform a crystallographic screening of a natural product-like fragment library against PKA.
• To identify novel fragments that bind to PKA, including those targeting the ATP site or allosteric sites.
• To characterize the binding modes and novelty of identified fragments.

Main Methods:

• High-performance soaking system for crystallographic screening of PKA.
• Fragment library screening using X-ray crystallography.
• Database mining, scaffold/chemotype analysis, and cheminformatics analyses.

Main Results:

• Resolved 36 fragment-bound PKA structures, achieving a 41% hit rate.
• Identified fragments binding to the ATP site, peripheral sites, or both.
• Discovered a fragment binding at the asciminib site and another inducing conformational changes.
• Confirmed novelty of fragments and their natural product parents regarding PKA interaction.
• Characterized fragments occupying a distinct chemical space with desirable drug-like properties.

Conclusions:

• The study identified novel PKA binders with unique chemical properties.
• These fragments represent promising starting points for developing selective and clinically successful kinase inhibitors.
• The identified fragments bind to distinct sites, including an allosteric site similar to asciminib, and induce conformational changes.