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的癌症类型之间差别很大。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，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)，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)携带者的亚群中，随后体细胞突变积累。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，这一存活率在过去30年中基本保持不变。明确和迫切需要确定和进行治疗这种疾病的新疗法的临床试验。虽然癌症是通过渐进性的体细胞突变发展的，但大量的临床前和临床研究表明，癌细胞依赖于相对较少的基因驱动事件。最近的研究对ATL和其他T细胞恶性肿瘤的基因变化进行了全面的分析，强调了这些潜在的致癌驱动基因突变。频繁的突变会影响对T细胞功能至关重要的不同成分，特别是与特定T细胞受体相关的细胞信号成分。最常突变的PLCG1基因编码磷脂酶C-γ1(PLC？1)，这是一种参与细胞内信号转导的酶。有几条证据支持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使用的大多数药物的分子靶点，主要基于小分子抑制剂，这一迄今尚未开发的靶点为开发亟需的新疗法提供了机会，用于治疗ATL、其他T细胞淋巴瘤和与PLC酶激活变体有关的其他几种疾病。我们不断努力的总体目标是创造一种小分子药物，可以作为单一药物使用，也可以作为不同治疗路线的联合药物使用。作为第一步，我们最近完成了对T细胞淋巴瘤中一种频繁突变的PLC？1变体的抑制物的大规模筛查。我们已经确定了几个有希望的化合物系列，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。为了实现这一点，我们建议应用药物化学，其中新化合物的设计由我们的结构、生物物理和计算工具辅助。与已有的类似物一起，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综合专业知识和跟踪记录，参与了我们之前和这次拟议的项目，广泛涵盖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。作为这项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方面的专业知识。这项提案所涵盖的步骤对于获得预期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方案进入下一个既定的进展阶段。

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.