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.

癌症治疗的进展在不同的癌症类型之间差异很大。对于许多类型的癌症，目前的干预措施大大延长了患者的生命，其他癌症，包括T细胞淋巴瘤，具有未满足的临床需求。T细胞淋巴瘤包括成人T细胞白血病/淋巴瘤（ATL），高度侵袭性恶性肿瘤，其在随后的体细胞突变积累之后出现在人T细胞嗜淋巴细胞病毒1型（HTLV-1）的携带者的子集中。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。有一个明确的和迫切的需要，以确定和进行临床试验的新疗法，这种疾病。尽管癌症通过进行性体细胞突变发展，但许多临床前和临床研究表明，癌细胞依赖于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，强调了此类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。最常突变的PLCG 1基因编码磷脂酶C γ 1（PLC？1），一种参与细胞内信号转导的酶。有几条支持证据表明，突变/激活的PLC变体？1有助于恶性ATL细胞的性质。考虑到细胞信号传导组分是大多数目前使用的药物的分子靶标，主要基于小分子抑制剂，这种迄今为止未开发的靶标为开发ATL，其他T细胞淋巴瘤和与PLC酶的活化变体相关的其他几种疾病的急需的新疗法提供了机会。我们不断努力的总体目标是产生一种小分子药物，其可以作为单一药物或作为组合药物用于不同的治疗线。作为第一步，我们最近完成了大规模的筛选抑制剂的频繁突变的PLC？1例T细胞淋巴瘤变异。我们已经确定了几个系列的有前途的化合物，以进一步优化和药物开发。我们现在计划扩大一个子集的命中化合物，并确定更有效和更有选择性的PLC抑制剂需要进一步的生物学评价和临床前研究。为了实现这一目标，我们建议应用药物化学，其中新化合物的设计是由我们的结构，生物物理和计算工具辅助的。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试验中测试这些新化合物。研究人员及其合作伙伴的综合专业知识和跟踪记录，参与了我们以前和这个拟议的项目，广泛涵盖了目标的分子和功能特性，药物化学和药物发现，以及ATL的临床前和临床方面。作为该提案的一个新组成部分，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。本提案所涵盖的步骤对于获得关于所需改进的可验证性的明确答案是必要的，这将导致通过药物发现计划进行下一个既定阶段。