Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation,Biochemistry

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Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation
Biochemistry ( IF 2.9 ) Pub Date : 2018-05-31 00:00:00 , DOI: 10.1021/acs.biochem.8b00391
Alexandru D. Buhimschi ₁ , Haley A. Armstrong ₂ , Momar Toure ₁ , Saul Jaime-Figueroa ₁ , Timothy L. Chen ₃ , Amy M. Lehman ₄ , Jennifer A. Woyach _{2,

3} , Amy J. Johnson ₃ , John C. Byrd _{2,

3} , Craig M. Crews _{1,

5,

6}

Affiliation

Inhibition of Bruton’s tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies, yet >80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist, and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK. We selected a lead PROTAC, MT-802, from several candidates on the basis of its potency to induce BTK knockdown. MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome. MT-802 binds fewer off-target kinases than ibrutinib does and retains an equivalent potency (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK. In cells isolated from CLL patients with the C481S mutation, MT-802 is able to reduce the pool of active, phosphorylated BTK whereas ibrutinib cannot. Collectively, these data provide a basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of C481S mutant CLL.

中文翻译：

使用PROTAC介导的降解靶向布鲁顿酪氨酸激酶中的C481S依鲁替尼耐药突变

不可逆抑制剂依鲁替尼抑制布鲁顿酪氨酸激酶（BTK）已成为慢性淋巴细胞性白血病（CLL）和其他B细胞恶性肿瘤患者的一种转化治疗选择，但超过80％的CLL患者由于半胱氨酸对依鲁替尼（C481S）共价结合的位点发生丝氨酸突变。目前，尚不存在对依鲁替尼复发的C481S患者的有效治疗选择，并且这些患者的预后较差。为了解决这个问题，我们开发了一种蛋白水解靶嵌合体（PROTAC），该酶诱导野生型和C481S突变体BTK的降解。我们根据潜在的诱因来诱导BTK的降低，从几名候选人中选择了领先的PROTAC MT-802。MT-802将BTK募集到大脑E3泛素连接酶复合体中，以通过蛋白酶体触发BTK泛素化和降解。与依鲁替尼相比，MT-802结合的脱靶激酶更少，并且针对野生型和C481S BTK保留了等效的效价（在纳摩尔浓度下，降解率> 99％）。在从具有C481S突变的CLL患者中分离的细胞中，MT-802能够减少活跃的磷酸化BTK库，而依鲁替尼则不能。总的来说，这些数据为进一步治疗BTK PROTAC的临床前研究提供了基础，作为治疗C481S突变体CLL的新策略。MT-802能够减少活性的磷酸化BTK库，而依鲁替尼则不能。总的来说，这些数据为进一步治疗BTK PROTAC的临床前研究提供了基础，作为治疗C481S突变体CLL的新策略。MT-802能够减少活性的磷酸化BTK库，而依鲁替尼则不能。总的来说，这些数据为进一步治疗BTK PROTAC的临床前研究提供了基础，作为治疗C481S突变体CLL的新策略。

更新日期：2018-05-31

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