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

MALT1 抑制剂用于治疗化疗耐药 ABC-DLBCL

• 批准号: 8924770
• 负责人: NATHANAEL Schiander GRAY
• 金额: $ 70.8万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924770
• 关键词: Accounting; Affect; Animals; B-Lymphocytes; BCR Signaling Pathway; Biochemistry; Biological; Biological Assay; Biological Availability; Biology; Boston; Cell Line; Cell Proliferation; Cell physiology; Cells; Clinic; Dana-Farber Cancer Institute; Data; Defect; Development; Disease; Dose; Drug Design; Drug Kinetics; Drug Targeting; Enzymes; Exhibits; Genetic; Gray unit of radiation dose; Growth; Half-Life; Hour; Human; In Vitro; Inhibitory Concentration 50; Lead; Modeling; Monitor; Mus; Names; Non-Hodgkin' s Lymphoma; Nuclear Translocation; Oral; Patients; Pediatric Hospitals; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmacodynamics; Plasma; Primary Neoplasm; Property; Rattus; Relative (related person); Reporting; Resistance; Resolution; Rodent; Safety; Sampling; Series; Structure; Survival Rate; T-Lymphocyte; Toxicology; Translations; Validation; Xenograft procedure; analog; base; chemotherapy; clinical investigation; design; enzyme activity; improved; in vivo; in vivo Model; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; lead series; medical schools; novel; outcome forecast; programs; protease XXIV; public health relevance; research study; response; small molecule; standard of care; structural biology; targeted treatment; therapeutic target; tool; tumor growth

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.

描述（由申请人提供）：弥漫性大 B 细胞淋巴瘤 (DLBCL) 是非霍奇金淋巴瘤最常见且最具侵袭性的亚型，占 DLBCL 中活化 B 细胞 (ABC) 亚型病例的 30% 至 40%。对当前护理标准的抵抗力最强，预后最差，5 年生存率仅为 35%，可识别潜在的遗传和功能异常。令人信服的证据表明，MALT1 是肿瘤生长和存活的关键效应酶，在两个主要的组成型活性 NF-κB 信号通路 BCR 和 TLR 之间形成关键节点。重要的是，MALT1 蛋白酶活性尤其已被证明对于肿瘤的存活至关重要。 ABC-DLBCL 细胞表明小分子 MALT1 抑制剂可能是这种 DLBCL 亚型的有效靶向治疗。此外，与蛋白酶一样，MALT1 是 ABC-DLBCL 治疗中有吸引力的酶。高度“可成药”的靶标和 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 抑制剂易于处理，不太可能对人类产生任何显着的有害影响。我们最近报道了 MI-2，这是唯一的一种。两种已报道的 MALT1 抑制剂类别。MI-2 抑制依赖于 MALT1 的 ABC-DLBCL 细胞系和异种移植物的生长，而对不依赖于 MALT 的细胞系几乎没有影响。此外，MI-2 还抑制增殖。总体而言，我们的结果对 MALT1 作为 ABC-DLBCL 的治疗靶点进行了相当多的药理学验证，以进一步评估 MALT1 作为 ABC-DLBCL 靶点的潜力和转化潜力。在我们的“主导”系列中，我们建议开发更有效、更具选择性的 MALT1 抑制剂，这些抑制剂具有改善的药代动力学特性和可接受的体外安全性，将在小鼠模型中评估其对 ABC-DLBCL 和原发性淋巴瘤的疗效。人类样本；顶级化合物将在为期两周的大鼠毒理学实验中进行进一步评估，以进行药物化学（Nathanel Gray 和 Sara Buhrlage，Dana-Farber 癌症研究所）、生物化学和结构生物学（吴浩（波士顿儿童医院））和 DLBCL 细胞生物学和药理学模型（Ari Melnick，威尔康奈尔医学院）需要对 ABC-DLBCL 中的 MALT1 进行药理学研究。