MALT1 inhibitors for the treatment of chemo-resistant ABC-DLBCL

摘要 弥漫性大B细胞淋巴瘤(DLBCL)是最常见和最具侵袭性的非霍奇金淋巴瘤亚型 淋巴瘤占病例的30%至40%。在DLBCL中，激活的B细胞(ABC)亚型最多 对目前的护理标准耐受，预后最差，5年存活率仅为35%。 对潜在的遗传和功能异常的识别提供了令人信服的证据，表明MALT1 是肿瘤生长和存活的关键效应酶，在两大肿瘤之间形成关键的结点 结构性激活的NF-8B信号通路BCR和TLR。重要的是，MALT1中的蛋白酶活性 已经证明特殊对ABC-DLBCL细胞的生存是必不可少的，这表明小分子 MALT1抑制剂可能是治疗该亚型DLBCL的有效靶向治疗药物。此外，MALT1是一种 用于ABC-DLBCL治疗的有吸引力的酶，因为酶是高度“可药物”的靶标和MALT1缺失的动物 除了B和T细胞功能缺陷外都是健康的，这表明选择性MALT1抑制剂是容易治疗的 而且不太可能对人类产生任何重大的有害影响。我们最近报道了MI-2，这是仅有的 已报道的两类MALT1抑制剂。MI-2抑制ABC-DLBCL细胞株的生长及对移植瘤的依赖 在MALT1上，而对不依赖MALT的细胞系几乎没有影响。此外，MI-2抑制血管紧张素转换酶 原代人DLBCL体外增殖，对小鼠无毒。总体而言，我们的结果提供了相当大的帮助 MALT1作为ABC-DLBCL治疗靶点的药理学验证。进一步评估...的潜力 作为ABC-DLBCL的目标的Malt1，以及我们计划开发的‘Lead’系列的翻译潜力 更有效和更有选择性的MALT1抑制剂，具有更好的药代动力学特性和可接受的 体外安全性简介。开发的抑制剂将在小鼠体内评估对ABC-DLBCL的疗效 模型和主要的人体样本；顶层化合物将在两周的大鼠中进一步评估 毒理实验。已经组建了一个多学科的团队来进行药物化学 (Dana-Farber癌症研究所Nathanael Gray和Sara Buhrlage)，生物化学和结构生物学(Hao 和DLBCL的细胞生物学和药理学模型(Ari Melnick，Weill 康奈尔医学院)被要求对ABC-DLBCL的MALT1进行药理学审问。

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive sub-type of non-Hodgkin lymphoma accounting for 30 to 40% of cases. Among DLBCLs the activated B-cell (ABC) subtype is the most resistant to the current standard of care and has the poorest prognosis with only a 35% 5-year survival rate. Identification of underlying genetic and functional abnormalities has provided compelling evidence that MALT1 is a critical effector enzyme of tumor growth and survival forming a critical node between the two major constitutively active NF-8B signaling pathways BCR and TLR. Importantly, the MALT1 protease activity in particular has been shown to be essential for survival of ABC-DLBCL cells suggesting that small molecule MALT1 inhibitors may be effective targeted therapy for this subtype of DLBCL. Furthermore, MALT1 is an attractive enzyme for ABC-DLBCL therapy as proteases are highly 'druggable' targets and MALT1-null animals are healthy aside from defects in B and T cell function suggesting that selective MALT1 inhibitors are tractable and unlikely to exert any significant deleterious effects in humans. We recently reported on MI-2, one of only two reported MALT1 inhibitor classes. MI-2 inhibits growth of ABC-DLBCL cell lines and xenografts dependent on MALT1 while exhibiting little to no effect on MALT independent cell lines. Furthermore, MI-2 inhibits the proliferation of primary human DLBCLs ex vivo and is non-toxic to mice. Overall our results lend considerable pharmacological validation of MALT1 as a therapeutic target in ABC-DLBCL. To further assess the potential of MALT1 as a target in ABC-DLBCL and the translational potential of our 'lead' series we propose to develop more potent and selective MALT1 inhibitors with improved pharmacokinetic properties and an acceptable in vitro safety profile. The developed inhibitors will be evaluated for efficacy against ABC-DLBCL in murine models and against primary human samples; top compounds will be further evaluated in a two-week rat toxicology experiment. A multi-disciplinary team has been assembled to perform the medicinal chemistry (Nathanael Gray and Sara Buhrlage, Dana-Farber Cancer Institute), biochemistry and structural biology (Hao Wu, Boston Children's Hospital), and cell biological and pharmacological models of DLBCL (Ari Melnick, Weill Cornell Medical College) required to pharmacologically interrogate MALT1 in ABC-DLBCL.