Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.

Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300–15. ©2018 AACR.

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不可逆抑制剂依鲁替尼对布鲁顿酪氨酸激酶（BTK）的靶向抑制可改善血液系统恶性肿瘤（包括慢性淋巴细胞性白血病）的患者的预后。在这里，我们描述了ARQ 531的临床前研究，ARQ 531是一种有效的，可逆的BTK抑制剂，对Src家族激酶和与ERK信号相关的激酶具有额外的活性。我们假设靶向其他激酶将改善信号通路的整体抑制，从而产生更强大的反应。用ARQ 531对患者CLL细胞进行体外治疗会降低BTK介导的功能，包括B细胞受体（BCR）信号传导，生存力，迁移，CD40和CD86表达以及NF-κB基因转录。体内，在CLL的鼠Eμ-TCL1植入模型和类似Richter转化的鼠Eμ-MYC/ TCL1植入模型中，发现ARQ 531比依鲁替尼提高生存率。另外，ARQ 531抑制CLL细胞存活并抑制BCR介导的C481S BTK和PLCγ2突变体的激活，这促进了对依鲁替尼的临床耐药性。

意义：这项研究表征了一种合理设计的激酶抑制剂，该模型在概述对依鲁替尼的获得性耐药的最常见机制的模型中具有功效。可逆的BTK抑制是对抗进行性CLL的一种有前途的策略，在Richter转化的情况下，多激酶抑制显示出比靶向依鲁替尼治疗优越的疗效。巨蟹座Discov; 8（10）; 1300–15。©2018 AACR。

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