Pirtobrutinib 是非共价的BTK选择性抑制剂，可抑制多种 BTK C481 替代突变。它对 BTK 的选择性是 370 种其他激酶的 300 倍以上，并且在 1 μM 时对非激酶靶点没有明显的抑制作用。它导致小鼠异种移植模型中 BTK 依赖性淋巴瘤肿瘤的消退。

Pirtobrutinib (LOXO-305), a highly selective and non-covalent next generation BTK inhibitor. Pirtobrutinib inhibits diverse BTK C481 substitution mutations. Pirtobrutinib causes regression of BTK-dependent lymphoma tumors in mouse xenograft models. Pirtobrutinib is also more than 300-fold selective for BTK versus 370 other kinases tested and shows no significant inhibition of non-kinase off-targets at 1 μM.

Pirtobrutinib potently inhibits both wild-type BTK and BTK C481S-mediated kinase activity with nanomolar potency. Pirtobrutinib strongly inhibits WT BTK (Y223) autophosphorylation with an IC50 of 3.68 nM. Pirtobrutinib inhibits BTK C481S Y223, C481T Y223, and C481R Y223 autophosphorylation with IC50s of 8.45, 7.23, and 11.73 nM, respectively[1].

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C22H21F4N5O3

479.436

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