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

描述（由申请人提供）：弥漫性大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤中最常见和侵袭性的亚型，占病例的30 - 40%。在DLBCL中，活化B细胞（ABC）亚型对当前标准治疗的抵抗力最强，预后最差，5年生存率仅为35%。潜在的遗传和功能异常的鉴定提供了令人信服的证据，即MALT 1是肿瘤生长和存活的关键效应酶，在两种主要的组成性活性NF-κB信号传导途径BCR和TLR之间形成关键节点。重要的是，MALT 1蛋白酶活性特别是已显示对于ABC-DLBCL细胞的存活是必需的，这表明小分子MALT 1抑制剂可能是这种DLBCL亚型的有效靶向疗法。此外，MALT 1是ABC-DLBCL治疗的有吸引力的酶，因为蛋白酶是高度“可药物化”的靶标，并且MALT 1缺失动物除了B和T细胞功能缺陷之外是健康的，这表明选择性MALT 1抑制剂是易处理的并且不太可能在人体中发挥任何显著的有害作用。我们最近报道了MI-2，这是仅有的两种MALT 1抑制剂之一。MI-2抑制依赖于MALT 1的ABC-DLBCL细胞系和异种移植物的生长，同时对MALT非依赖性细胞系表现出很小的影响或没有影响。此外，MI-2离体抑制原代人DLBCL的增殖，并且对小鼠无毒。总的来说，我们的结果提供了相当大的药理学验证MALT 1作为ABC-DLBCL的治疗靶点。为了进一步评估MALT 1作为ABC-DLBCL靶点的潜力和我们的“先导”系列的翻译潜力，我们建议开发具有改善的药代动力学特性和可接受的体外安全性特征的更有效和选择性的MALT 1抑制剂。将在小鼠模型和主要人类样品中评估开发的抑制剂对ABC-DLBCL的功效;将在为期两周的大鼠毒理学实验中进一步评估顶级化合物。已经组建了一个多学科团队来执行药物化学（Nathanael Gray和Sara Buhrlage，Dana-Farber癌症研究所），生物化学和结构生物学（Hao Wu，波士顿儿童医院）以及DLBCL的细胞生物学和药理学模型（Ari Melnick，Weill Cornell医学院），这些模型需要在ABC-DLBCL中重新询问MALT 1。

DESCRIPTION (provided by applicant): 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-κB 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.