Inhibition of platelet kinase signaling and scaffolding activities with small molecule proteolysis-targeting chimeras (PROTACs)

作者：Eliana Choi, Yiheng Zhang, Raquel Mote, Vrishank Shivaprakash, Alexander R. Melrose, H A Capell, Owen J. T. McCarty, Joseph E. Aslan · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-3020 · 被引用次数：1 · 研究领域：Protein Degradation and Inhibitors、HER2/EGFR in Cancer Research、Multiple Myeloma Research and Treatments

Abstract Tyrosine kinase inhibitors (TKIs) play an expanding role in treating cancers and other diseases, including thromboinflammatory and vascular conditions. However, many TKIs cause off-target or toxic effects in healthy cells of the blood and vascular systems especially platelets, as bleeding and thrombotic complications are commonly associated with TKIs in and out of clinical trials. Bleeding risks are particularly notable for patients with B cell malignancies treated with TKIs such as ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. Studies over the past decade have detailed how ibrutinib and other BTK inhibitors disrupt platelet function through direct (“on-target”) and indirect (“off-target”) mechanisms. In contrast, many TKIs targeting other kinase activities do not appear to carry the same bleeding risks as BTK inhibitors, highlighting the diversity of kinase function in blood cells. For example, Abl inhibitor asciminib does not affect platelet function and is not associated with bleeding, while other Abl inhibitors like ponatinib abrogate platelet function and increase risk of thrombosis. Beyond off-target toxicities of TKIs, evolving therapeutic resistances to TKIs present challenges in the clinic, fueling the need for novel agents to modulate signaling systems in disease. Small molecule proteolysis-targeting chimeras (PROTACs), which specifically target proteins for degradation rather than merely inhibiting their signaling activities, have emerged as agent...