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很大变化。对于许多类型的癌症，目前的干预措施大大延长了患者的寿命，包括T细胞淋巴瘤在内的其他癌症具有未满足的临床需求。 T细胞淋巴瘤包括成年T细胞白血病/淋巴瘤（ATL），在随后的体细胞突变堆积之后，在人类T细胞淋巴细胞病毒1型（HTLV-1）的一部分中产生的高度侵略性恶性肿瘤。侵略性亚型的总体生存期为〜9-13个月，令人沮丧的是，由于当前的治疗选择，在过去30年中，这种存活率在很大程度上保持不变。明确而迫切需要识别和进行该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而发展的，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因素。最近的研究提供了对ATL和其他T细胞恶性肿瘤的遗传变化的全面分析，突出了这种潜在的致癌驱动器突变。频繁的突变会影响对T细胞功能重要的不同成分，尤其是与特定T细胞受体相关的细胞信号传导成分。最常突变的PLCG1基因编码磷脂酶C伽马1（PLC？1），这是一种参与细胞内信号转导的酶。有几条支持证据表明，PLC的突变/激活变体有助于恶性，ATL细胞的特性。考虑到细胞信号传导成分是大多数当前使用的药物的分子靶标，主要基于小分子抑制剂，因此，这个迄今未开发的靶标提供了一个机会，为开发了急需的新型ATL疗法，其他T细胞淋巴瘤，其他几种与PLC Enzymes激活变体相关的其他疾病。我们持续努力的总体目的是生成一种小分子药物，该药物可以用作单一药物或在不同的治疗方案中用作联合剂。作为第一步，我们最近完成了大规模筛选，用于在T细胞淋巴瘤中经常突变的PLC？1变体的抑制剂。我们已经确定了几种有希望的化合物，以进一步优化和药物开发。现在，我们计划扩展一部分命中化合物，并确定进一步的生物学评估和临床前研究所需的更有效和更具选择性的PLC抑制剂。为了实现这一目标，我们建议采用药物化学，在我们的结构，生物物理和计算工具的协助下设计新化合物。加上已经可用的类似物，我们将在我们已建立的体外和基于细胞的测定中测试这些新化合物。研究人员及其合作伙伴的联合专业知识和追踪记录涉及我们以前的和拟议的项目，广泛涵盖了目标的分子和功能性能，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有关的基于人工智能方法的专业知识。该提案所涵盖的步骤对于获得有关所需改进的确定答案是必要的，这将导致通过药物发现计划的下一个建立阶段。