Protein phosphorylation is dynamically controlled by kinases and phosphatases, and its dysregulation contributes to diverse disease-relevant states. Although conventional kinase modulators have enabled important therapeutic advances, direct kinase or phosphatase modulation often lacks the precision needed to correct phosphorylation at the level of a defined protein of interest (POI). Proximity-inducing modalities, particularly phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase-recruiting chimeras (PHORCs), offer an event-driven strategy to modulate phosphorylation by recruiting catalytic effectors to selected targets. Recent studies have extended PHICSs beyond early proof-of-concept systems, highlighting both improved pan-AMPK recruitment strategies and self-recruiting designs that redirect oncogenic kinase activity toward inhibitory phosphorylation. In parallel, recent PHORC studies have diversified induced dephosphorylation, spanning tag-based signaling rewiring, simultaneous PP5 recruitment and activation, and aptamer-guided PTPRF recruitment for receptor regulation. Together, these studies highlight the expanding scope of proximity-induced phosphorylation control, while emphasizing that broader application will depend on improved molecular design and a clearer understanding of proximity-driven mechanisms.
Yuxin Xia, Daichao Zhai, Qi-Dong You et al.· RSC Medicinal Chemistry· 0 citations
Covalent inhibitors bind tightly and persistently to protein targets via covalent links with nucleophilic amino acids, yet unintended covalent modification of irrelevant proteins creates major safety risks and restricts their clinical use. To tackle this issue, researchers have shifted from reactivity-centered design to selectivity-prioritized engineering, a core trend in this field over the last five years. This review summarizes five synergistic tactics to boost covalent inhibitor selectivity. First, strengthening noncovalent binding affinity accurately positions reactive warheads for target residues and lowers off-target interactions. Second, redesigned warheads - new electrophiles for non-cysteine sites and reversible covalent groups with adjustable binding duration - broaden druggable proteins and separate target and off-target binding via kinetic differences. Third, leveraging distinct nucleophilic microenvironments (isoform-specific amino acid variations, allosteric cavities, mutation-generated residues) enhances target-specific recognition. Fourth, structure-based tuning of warhead spatial shapes controls covalent reaction efficiency and selectivity. Fifth, prodrugs deliver active inhibitors locally at disease sites with temporal and spatial precision. Collectively, these innovations validate kinact/Ki as a unified rule balancing efficacy and selectivity. With advancing proteome profiling, computational warhead modeling and conditional electrophile chemistry, covalent inhibitors will tackle hard-to-drug targets with safety comparable to noncovalent medicines.
Shang-Jun Bai, Meng-Han Gao, Qi-Dong You et al.· European journal of medicina...· 0 citations
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