Cell-Active, Irreversible Covalent Inhibitors Targeting a Surface-Exposed Non-Catalytic Lysine on Aurora a Kinase by...

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Targeting surface-exposed lysines in kinases for covalent modification is challenging due to their low reactivity and high pKa.
• Current covalent kinase inhibitors (CKIs) primarily target reactive lysines within the ATP-binding pocket, neglecting surface-exposed ones.

Purpose of the Study:

• To develop a systematic and rational strategy for selectively targeting surface-exposed, non-catalytic lysines in kinases.
• To establish squarate chemistry as a versatile platform for creating cell-active CKIs.

Main Methods:

• Utilized squarate chemistry to develop covalent inhibitors targeting surface-exposed lysines.
• Employed Aurora A kinase (AURKA) as a model system for proof-of-concept studies.
• Compared squarates with other lysine-reactive warheads (EBA, SO2F, OSO2F) for efficacy.

Main Results:

• Demonstrated superior efficacy of squarates in engaging low-reactivity, surface-exposed lysines compared to other warheads.
• Developed AL8, the first cell-active, squarate-based CKI targeting AURKA with high selectivity and long residence time.
• Investigated the impact of leaving groups on squaric esters, providing insights for CKI development.

Conclusions:

• Squarate chemistry provides a unique and tunable platform for covalent modification of surface-exposed lysines in kinases.
• This strategy enables the development of novel CKIs for targeted kinase drug discovery, addressing previously inaccessible targets.