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

癌症治疗的进展在不同类型的癌症之间差别很大。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，有一个未满足的临床需求。t细胞淋巴瘤包括成人t细胞白血病/淋巴瘤（ATL），这是一种高度侵袭性的恶性肿瘤，发生在人类t细胞嗜淋巴病毒1型（HTLV-1）的携带者亚群中，随后是体细胞突变的积累。侵袭性亚型的中位总生存期为~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。明确而迫切地需要确定并开展针对这种疾病的新疗法的临床试验。虽然癌症是通过渐进的体细胞突变发展的，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成分。最常发生突变的PLCG1基因编码磷脂酶C γ 1 (PLC？1)，参与细胞内信号转导的酶。有几条线的支持证据表明，突变/激活的PLC？1有助于恶性ATL细胞的特性。考虑到细胞信号传导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，这一迄今未开发的靶点为开发ATL、其他t细胞淋巴瘤和其他几种与PLC酶激活变体相关的疾病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，可以作为单一药物或作为联合药物，用于不同的治疗方法。作为第一步，我们最近完成了对一种频繁突变的PLC？t细胞淋巴瘤的1个变异。我们已经确定了几个有前途的化合物系列，用于进一步优化和药物开发。我们现在计划扩大hit化合物的子集，并确定更有效和更具选择性的PLC抑制剂，以进行进一步的生物学评估和临床前研究。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协助。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分析中测试这些新化合物。研究人员及其合作伙伴的专业知识和业绩记录，参与了我们之前和这个拟议的项目，广泛涵盖了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。作为本提案的新组成部分，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。本建议所涵盖的步骤对于获得关于预期改进能否实现的明确答案是必要的，这将通过药物发现规划导致进展的下一个既定阶段。

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.