Optimisation of small molecule inhibitors for effective targeting of phospholipase C gamma in T-cell lymphoma

优化小分子抑制剂以有效靶向 T 细胞淋巴瘤中的磷脂酶 C γ

• 批准号: MR/Y503344/1
• 负责人: Matilda Katan
• 金额: $ 31.5万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY503344%2F1
• 关键词: Optimisation; small; molecule; inhibitors; effective

Progress in cancer treatment very much varies between different cancer types. For many types of cancer, the current interventions considerably prolong lives of patients, other cancers, including T-cell lymphomas, have an unmet clinical need. T-cells lymphomas include adult T-cell leukemia/lymphoma (ATL), highly aggressive malignancy that arises in a subset of carriers of human T-cell lymphotropic virus type 1 (HTLV-1), following subsequent accumulation of somatic mutations. The median overall survival of aggressive subtypes is ~9-13 months and depressingly, with current treatment options, this survival rate has remained largely unchanged in the past 30 years. There is a clear and urgent need to identify and conduct clinical trials of novel therapies for this disease. Although cancer develops through progressive somatic mutations, numerous preclinical and clinical studies have shown that cancer cells depend on relatively few genetic driver events. Recent studies have provided comprehensive analyses of the genetic changes in ATL and other T-cell malignancies, highlighting such potential oncogenic driver mutations. Frequent mutations affect different components important for T-cell functions and, in particular, cell signalling components linked to specific T-cell receptors. The most frequently mutated PLCG1 gene encodes phospholipase C gamma 1 (PLC?1), an enzyme involved in intracellular signal transduction. There are several lines of supporting evidence that mutated/activated variants of PLC?1 contribute to the properties of the malignant, ATL cells. Considering that cell signalling components are the molecular targets of most currently used medicines, largely based on small-molecule inhibitors, this so far unexploited target provides an opportunity to develop much needed novel therapies for ATL, other T-cell lymphoma and several other diseases linked to activated variants of PLC enzymes. The overall aim of our continuous efforts is to generate a small molecule drug that can be used as a single agent, or as a combination agent, in different lines of therapy. As a first step, we recently completed large-scale screens for inhibitors of a frequently mutated PLC?1 variant in T-cell lymphoma. We have identified several series of promising compounds for further optimisation and drug development. We now plan to expand a subset of hit compounds and identify more potent and more selective PLC inhibitors needed for further biological evaluation and preclinical studies. To achieve this, we propose to apply medicinal chemistry, where design of new compounds is assisted by our structural, biophysical, and computational tools. Together with already available analogues, we will test these new compounds in our established in vitro and cell-based assays. The combined expertise and track record of investigators and their partners, involved in our previous and this proposed project, extensively covers molecular and functional properties of the target, medicinal chemistry and drug discovery, and preclinical and clinical aspects of ATL. As a new component of this proposal, we also include expertise in artificial intelligence-based methods related to drug discovery. The step covered by this proposal is necessary to obtain definitive answers about achievability of desired improvements, which will lead to the next established stages in progression through a drug discovery programme.

不同癌症类型的癌症治疗进展差异很大。对于许多类型的癌症，目前的干预措施可显着延长患者的生命，但包括 T 细胞淋巴瘤在内的其他癌症的临床需求尚未得到满足。 T 细胞淋巴瘤包括成人 T 细胞白血病/淋巴瘤 (ATL)，这是一种高度侵袭性的恶性肿瘤，由人类 T 细胞嗜淋巴细胞病毒 1 型 (HTLV-1) 携带者亚群在随后体细胞突变积累后产生。侵袭性亚型的中位总生存期约为 9-13 个月，令人沮丧的是，在目前的治疗方案下，这一生存率在过去 30 年中基本保持不变。显然，迫切需要确定并进行针对这种疾病的新疗法的临床试验。尽管癌症是通过进行性体细胞突变发展的，但大量临床前和临床研究表明，癌细胞依赖相对较少的遗传驱动事件。最近的研究对 ATL 和其他 T 细胞恶性肿瘤的遗传变化进行了全面分析，强调了这种潜在的致癌驱动突变。频繁的突变会影响对 T 细胞功能重要的不同成分，特别是与特定 T 细胞受体相关的细胞信号传导成分。最常见突变的 PLCG1 基因编码磷脂酶 C gamma 1 (PLC?1)，一种参与细胞内信号转导的酶。有多种支持证据表明 PLC?1 的突变/激活变体有助于恶性 ATL 细胞的特性。考虑到细胞信号成分是目前大多数使用的药物的分子靶点，主要基于小分子抑制剂，这一迄今为止尚未开发的靶点为开发急需的 ATL、其他 T 细胞淋巴瘤和其他几种相关疾病的新疗法提供了机会。 PLC 酶的激活变体。我们不断努力的总体目标是生产一种小分子药物，可以在不同的治疗方案中作为单一药物或组合药物使用。作为第一步，我们最近完成了 T 细胞淋巴瘤中频繁突变的 PLC?1 变体抑制剂的大规模筛选。我们已经确定了几个有前景的化合物系列，用于进一步优化和药物开发。我们现在计划扩大热门化合物的子集，并确定进一步生物学评估和临床前研究所需的更有效、更具选择性的 PLC 抑制剂。为了实现这一目标，我们建议应用药物化学，在我们的结构、生物物理和计算工具的帮助下设计新化合物。与现有的类似物一起，我们将在我们建立的体外和基于细胞的测定中测试这些新化合物。参与我们之前和本拟议项目的研究人员及其合作伙伴的综合专业知识和跟踪记录广泛涵盖靶点的分子和功能特性、药物化学和药物发现以及 ATL 的临床前和临床方面。作为该提案的新组成部分，我们还包括与药物发现相关的基于人工智能的方法的专业知识。该提案涵盖的步骤对于获得有关所需改进的可实现性的明确答案是必要的，这将导致通过药物发现计划进入下一个既定阶段。