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

描述(申请人提供)：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，占病例的30%至40%。在DLBCL中，活化的B细胞(ABC)亚型对当前治疗标准的抵抗力最强，预后最差，5年存活率仅为35%。对潜在的遗传和功能异常的鉴定已经提供了令人信服的证据，表明MALT1是肿瘤生长和生存的关键效应酶，形成了两个主要的结构性活性的NF-κB信号通路Bcr和Tlr之间的关键节点。重要的是，MALT1蛋白水解酶的活性对ABC-DLBCL细胞的存活至关重要，提示小分子MALT1抑制剂可能是这一亚型DLBCL的有效靶向治疗。此外，MALT1是一种有吸引力的酶，用于ABC-DLBCL治疗，因为蛋白酶是高度“可用药”的靶标，并且MALT1缺失的动物除了B和T细胞功能缺陷外是健康的，这表明选择性MALT1抑制剂是容易处理的，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，这是仅有的两个已报道的MALT1抑制剂类别之一。MI-2抑制依赖MALT1的ABC-DLBCL细胞和异种移植瘤的生长，而对MALT非依赖的细胞株几乎没有影响。此外，MI-2在体外可抑制原代培养的人DLBCL的增殖，对小鼠无毒。总体而言，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‘Lead’系列的翻译潜力，我们建议开发更有效和更具选择性的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。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的有效性；TOP化合物将在为期两周的大鼠毒理学实验中进一步评估。已经组建了一个多学科团队来进行药物化学(Dana-Farber癌症研究所的Nathael Gray和Sara Buhrlage)、生物化学和结构生物学(Hao Wu，波士顿儿童医院)以及DLBCL(Ari Melnick，威尔·康奈尔医学院)的细胞生物学和药理学模型，以药理学地询问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.