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、最具侵袭性的亚型，约占病例的30 - 40%。在dlbcl中，活化b细胞（ABC）亚型对目前的标准治疗最具耐药性，预后最差，5年生存率仅为35%。发现潜在的遗传和功能异常提供了令人信服的证据，证明MALT1是肿瘤生长和存活的关键效应酶，在两种主要的构成活性NF-κB信号通路BCR和TLR之间形成关键节点。重要的是，MALT1蛋白酶活性已被证明对ABC-DLBCL细胞的存活至关重要，这表明小分子MALT1抑制剂可能是这种DLBCL亚型的有效靶向治疗。此外，MALT1是一种有吸引力的用于ABC-DLBCL治疗的酶，因为蛋白酶是高度“可药物化”的靶标，而且MALT1缺失的动物除了B细胞和T细胞功能缺陷外都是健康的，这表明选择性MALT1抑制剂是可控制的，不太可能对人类产生任何显著的有害影响。我们最近报道了MI-2，这是仅有的两种MALT1抑制剂之一。MI-2抑制依赖于MALT1的ABC-DLBCL细胞系和异种移植物的生长，而对MALT不依赖的细胞系几乎没有影响。此外，MI-2还能抑制人原发性dlbcl的体外增殖，对小鼠无毒。总的来说，我们的结果为MALT1作为ABC-DLBCL的治疗靶点提供了相当大的药理学验证。为了进一步评估MALT1作为ABC-DLBCL靶点的潜力和我们的“先导”系列的转化潜力，我们建议开发更有效和选择性的MALT1抑制剂，改善药代动力学特性和可接受的体外安全性。开发的抑制剂将在小鼠模型和原始人类样本中评估对ABC-DLBCL的疗效；顶级化合物将在为期两周的大鼠毒理学实验中进一步评估。我们组建了一个多学科的团队，进行药物化学（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）所需的药理学研究ABC-DLBCL中的MALT1。

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.