Hit expansion of allosteric GALK1 inhibitors for galactosemia

半乳糖血症变构 GALK1 抑制剂的命中扩展

• 批准号: MR/Z503708/1
• 负责人: Wyatt Yue
• 金额: $ 31.47万
• 依托单位: Newcastle University
• 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%2FZ503708%2F1
• 关键词: Hit; expansion; allosteric; GALK1; inhibitors

Classic galactosemia is a rare disorder of galactose metabolism, with very disappointing outcomes, representing a heavy burden on the patients' quality of life and on the healthcare systems. Its current standard of care, a galactose-restricted diet, fails to prevent cognitive, neurological, social and fertility impairments. This proposal aims to advance the frontiers of galactosemia successful treatment, using a small molecule-based approach.Our approach aims to address the root cause of disease, which is the toxic accumulation of galactose-1-phosphate, through inhibiting the GALK1-catalysed biosynthesis of this metabolite. GALK1 (galactokinase 1) is a valued, validated therapeutic target, with demonstrated proof of concept in cell-based and animal disease models.Our proposal applies structural based approaches towards hit optimisation of GALK1 inhibitors, combining expertise and track record in computational chemistry (Daniel Cole), medicinal chemistry (Celine Cano) and structural biology (Wyatt Yue) at Newcastle University.Prior to this proposal, our project team has:established GALK1 protein production, activity and binding assays, and co-crystal structure determination in place for a drug discovery programme;identified and verified three compound series able to inhibit GALK1 via an allosteric binding mode;applied computational de novo design, docking and molecular dynamics to optimise ligand design towards targeting GALK1; andprogressed, using fewer than 60 follow-up compounds, from inactive fragments to three promising inhibitory series, enabled by computational and medicinal chemistry, and enriched through a wealth of co-structures.Through 3 work packages, our project team will apply computational and medicinal chemistry approaches to the design and generation of new compounds based on our chemical starting points, and characterise the binding, potency, and selectivity of these compounds in biophysical and structural assays. Based on the assay profiles we will identify one series for focused efforts to fine-tune compounds through design-synthesis-assay cycles. Finally, we will determine the ability of our best compounds to target GALK1 and generate functional impact in human cells.Through this proposal we set out to de-risk early-stage drug discovery for a rare disease, to advance our chemical starting points into validated hits, and to deliver a promising compound paving the route for lead development.There is a clear downstream pathway for development:Through engagement with US-based Galactosemia Foundation and the EU-based Galactosemia Network, the project lead has networked and collaborated with clinical and research leaders in the field (Bosch, Amsterdam; Gozalbo-Rubio, Maastricht; Riviera, Lisbon; Treacy, Dublin; Lai, Utah). These collaborators will be key to characterising our lead inhibitors arising from this proposal in their cell-based (patient-derived fibroblast and iPSC lines) and organism (zebrafish, mouse) models of disease for in vitro and in vivo efficacy through metabolic flux, enzyme activity and phenotypic analyses. Additionally, we have identified and engaged in discussion with biotech/pharma partners with potential interest in the GALK1 inhibitor programme. Working together, our vision is a first-in-class small molecule inhibitor to treat classic galactosemia.

典型半乳糖血症是一种罕见的半乳糖代谢紊乱，具有非常令人失望的结果，对患者的生活质量和医疗保健系统造成沉重负担。其目前的护理标准，半乳糖限制饮食，未能预防认知，神经，社会和生育障碍。该提案旨在使用基于小分子的方法推进半乳糖血症成功治疗的前沿。我们的方法旨在通过抑制GALK 1催化的这种代谢物的生物合成来解决疾病的根本原因，即半乳糖-1-磷酸的毒性积累。GALK1半乳糖激酶1（galactokinase 1）是一个有价值的、经过验证的治疗靶点，在细胞和动物疾病模型中已经证明了这一点。我们的建议将基于结构的方法应用于GALK 1抑制剂的命中优化，结合了计算化学方面的专业知识和跟踪记录。（丹尼尔科尔），药物化学（Celine Cano）和结构生物学（Wyatt Yue）在纽卡斯尔大学。在此之前，我们的项目团队已经：建立GALK 1蛋白生产、活性和结合测定，以及药物发现计划的共晶体结构测定;鉴定并验证了三个能够通过变构结合模式抑制GALK 1的化合物系列;应用计算从头设计、对接和分子动力学来优化靶向GALK 1的配体设计;和进步，使用不到60个后续化合物，从非活性片段到三个有前途的抑制系列，通过计算和药物化学实现，并通过丰富的共结构进行丰富。通过3个工作包，我们的项目团队将应用计算和药物化学方法，根据我们的化学起点设计和生成新化合物，并在生物物理和结构分析中验证这些化合物的结合力，效力和选择性。基于分析概况，我们将确定一个系列，通过设计-合成-分析循环集中精力微调化合物。最后，我们将确定我们最好的化合物靶向GALK 1并在人体细胞中产生功能影响的能力。通过这一提议，我们着手降低罕见疾病早期药物发现的风险，将我们的化学起点推进到验证的命中，并提供一种有前途的化合物，为先导开发铺平道路。通过与美国的半乳糖血症基金会和欧盟的半乳糖血症网络的合作，项目负责人与该领域的临床和研究领导者（阿姆斯特丹的Bosch;马斯特里赫特的Gozalbo-Rubio;里斯本的里维埃拉;都柏林的Treacy;犹他州的Lai）建立了网络并进行了合作。这些合作者将是通过代谢通量、酶活性和表型分析，在基于细胞的（患者来源的成纤维细胞和iPSC系）和生物体（斑马鱼、小鼠）疾病模型中表征我们的主要抑制剂的关键，以获得体外和体内疗效。此外，我们已经确定并与对GALK 1抑制剂项目有潜在兴趣的生物技术/制药合作伙伴进行了讨论。通过共同努力，我们的愿景是开发出一流的小分子抑制剂，用于治疗典型的半乳糖血症。