SIRT2 Inhibitors for the Treatment of B-cell Lymphoma

我们建议开发NAD+依赖性脱乙酰酶SIRT 2抑制剂作为新的，靶向的，无毒的 在一些实施方案中，本发明涉及抑制BCL 6的化疗剂，BCL 6是B细胞淋巴瘤中肿瘤发生的关键驱动因素。共同 已经通过大规模的研究鉴定了生殖中心B细胞来源的淋巴瘤的遗传驱动因素 排序的努力。然而，将这些知识转化为新的疗法仍然具有挑战性，特别是 对于驱动因子缺失且有效治疗靶标不能立即 明显高达40%的生发中心来源的淋巴瘤，包括侵袭性、弥漫性大B细胞淋巴瘤和非侵袭性淋巴瘤。 淋巴瘤（DLBCL）和惰性滤泡细胞淋巴瘤（FL），包含组蛋白功能缺失突变 乙酰基转移酶（HAT），CREBBP和p300，使HAT中的功能丧失突变成为最常见的 淋巴瘤中常见的遗传变异因此，针对这些基因改变的治疗可能会有所帮助。 大部分淋巴瘤患者。 虽然HAT中的功能缺失突变在其他癌症中的频率很低，但它们的异常 DLBCL和FL的高患病率表明乙酰化失调在发病机制中起着重要作用 源自生殖中心的恶性肿瘤细胞HAT活性的降低与 淋巴瘤发生的两种关键介质BCL 6和p53的调节异常， 和低活性，分别由低乙酰化状态。我们发现药理学抑制SIRT 2 抵消了蛋白质乙酰化失衡，驱动淋巴瘤，从而构成了一个新的 用于治疗生发中心来源的淋巴瘤的治疗策略。我们的初步数据证实了这一点 治疗策略，并提供证据表明，通过SIRT 2抑制BCL 6失活构成了基础 抗淋巴瘤活性基于这一基本原理和我们的初步数据，我们建议：优化SIRT 2 使用药物化学和基于结构的药物设计的抑制剂;确定SIRT 2 抑制剂消除了BCL 6功能，并显示出体内抗淋巴瘤活性。因此，我们将 提供一种新的治疗策略，并开发小分子SIRT 2抑制剂，靶向最重要的疾病之一， 在生发中心衍生的恶性肿瘤中常见的遗传改变。

We propose to develop inhibitors of NAD+-dependent deacetylase SIRT2 as new, targeted, non-toxic chemotherapeutic agents that inactivate BCL6, a key driver of tumorigenesis in B-cell lymphoma. Common genetic drivers for germinal center B cell-derived lymphomas have be identified through large scale sequencing efforts. However, transferring this knowledge into novel therapies remains challenging, particularly for loss-of-function mutations where the driver is absent and a valid therapeutic target is not immediately obvious. Up to 40% of germinal center-derived lymphomas, including both aggressive, diffuse large B-cell lymphoma (DLBCL), and indolent, follicular cell lymphoma (FL), contain loss of function mutations in histone acetyl transferases (HATs), CREBBP and p300, making loss-of-function mutations in HATs among the most common genetic alterations in lymphoma. Therapies aimed at these genetic alterations may therefore help large fraction of lymphoma patients. While loss of function mutations in HATs can be found at low frequency in other cancers, their extraordinarily high prevalence in DLBCL and FL suggests a fundamental role of dysregulated acetylation in the pathogenesis of germinal center-derived malignancies. Reduced activity of cellular HATs has been implicated in dysregulation of two critical mediators of lymphomagenesis, BCL6 and p53, which are rendered hyperactive and hypoactive, respectively, by the hypoacetylated state. We show that pharmacological inhibition SIRT2 counteracts the protein acetylation imbalance that drives lymphomagenesis, and thus constitutes a novel therapeutic strategy for treatment of germinal center-derived lymphomas. Our preliminary data validate this therapeutic strategy and provide evidence that BCL6 inactivation through SIRT2 inhibition consititues the basis for the anti-lymphoma activity. Based on this rationale and our preliminary data, we propose to: optimize SIRT2 inhibitors using medicinal chemistry and structure-based drug design; identify the mechanisms by which SIRT2 inhibitors abrogates BCL6 function, and; demonstrate in vivo anti-lymphoma activity. As a result, we will provide a novel therapeutic strategy and develop small molecule SIRT2 inhibitors, targeting one of the most common genetic alterations in germinal center-derived malignancies.