Pirtobrutinib抑制野生型和突变体布鲁顿在慢性淋巴细胞白血病的酪氨酸kinase-mediated信号。
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阿斯兰B, Kismali G, Iles LR, Manyam GC, Ayres ML,陈LS Gagea M, Bertilaccio MTS, Wierda WG,甘地V
Pirtobrutinib抑制野生型和突变体布鲁顿在慢性淋巴细胞白血病的酪氨酸kinase-mediated信号。
血癌j . 2022年5月20日,12 (5):80。doi: 10.1038 / s41408 - 022 - 00675 - 9。
- PubMed ID
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35595730 (在PubMed]
- 文摘
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Pirtobrutinib (loxo - 305),一个可逆抑制剂布鲁顿的酪氨酸激酶(对)杀人案,被设计成另外一个策略来治疗ibrutinib-resistant疾病发展由于C481激酶结构域突变。pirtobrutinib已经证明在慢性淋巴细胞白血病的临床活动,但作用机制尚未研究。我们评估pirtobrutinib 4模型系统:首先,MEC-1,慢性淋巴细胞白血病细胞系overexpressing对(WT),杀人案对(C481S)杀人案,或对(C481R)杀人案;第二,小鼠模型由MEC-1 overexpressing对(WT)或对(C481S);杀人案杀人案第三,主要慢性淋巴细胞白血病细胞的体外孵化项目;最后,慢性淋巴细胞白血病患者在pirtobrutinib疗法(NCT03740529 ClinicalTrials.gov)。Pirtobrutinib抑制对激活以及下游信号杀人案MEC-1 overexpressing同基因的细胞对(WT),杀人案对(C481S)杀人案,或对(C481R)杀人案。在老鼠身上,总生存期短是因为积极的疾病。Pirtobrutinib治疗2周导致脾脏和肝脏重量的减少对(WT)和杀人案对(C481S)细胞,杀人案。慢性淋巴细胞白血病细胞的体外孵化项目窝藏野生型或突变体对抑制BCR通路的杀人案ibrutinib或pirtobrutinib治疗。 Pirtobrutinib therapy resulted in inhibition of BTK phosphorylation and downstream signaling initially in all cases irrespective of their BTK profile, but these effects started to revert in cases with other BCR pathway mutations such as PLCG2 or PLEKHG5. Levels of CCL3 and CCL4 in plasma were marginally higher in patients with mutated BTK; however, there was a bimodal distribution. Both chemokines were decreased at early time points and mimicked BCR pathway protein changes. Collectively, these results demonstrate that pirtobrutinib is an effective BTK inhibitor for CLL harboring wild-type or mutant BTK as observed by changes in CCL3 and CCL4 biomarkers and suggest that alterations in BCR pathway signaling are the mechanism for its clinical effects. Long-term evaluation is needed for BTK gatekeeper residue variation along with pathologic kinase substitution or mutations in other proteins in the BCR pathway.
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