Chemoproteomics identifies a pyrimido[4,5- d ]pyrimidine analogue as a tubulin-tyrosine ligase binder

Le résumé fourni par la source

Abstract Small-molecule drug discovery relies on identifying compounds that modulate specific protein targets, a process often hindered by cellular complexity. Through phenotypic screening of a kinase-focused diazaquinazoline library, we serendipitously identified CEM198 as the first high-affinity ligand of tubulin-tyrosine ligase (TTL). Functional assays combining live-cell TTL inhibition, microtubule polymerization, cell cycle analysis, and proteomics revealed that CEM198 acts through a dual mechanism: directly binding to TTL and altering α/β-tubulin conformation. This interaction restricts α-tubulin tyrosination and disrupts tubulin polymerization, leading to microtubule destabilization. The differential effects observed between SH-SY5Y and HEK293T cells indicate that effective TTL inhibition depends on both direct binding and structural modulation of the tubulin heterodimer. These findings introduce CEM198 as a chemical probe for investigating the tubulin tyrosination–detyrosination and demonstrate the potential of chemoproteomics to uncover novel modulators of microtubule dynamics.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.