Development of Small Molecule degraders of ILK for glioblastoma therapy

多形性胶质母细胞瘤（GBM）是成人中最常见和侵袭性的恶性原发性脑肿瘤，其基本上是不可治愈的，从诊断开始的中位生存期约为12-18个月。迫切需要鉴定和验证新的分子靶点，以揭示GBM亚型之间的共同生物学脆弱性，并设计新的治疗策略。整合素连接激酶（ILK）是整合素下游的一种神秘的假激酶，其驱动恶性GBM并作为潜在的有价值的靶点。尽管不可药用的ILK缺乏催化活性，但Unciti-Broceta教授和Frame教授已经确定了一种新的化学策略，通过靶向其伪激酶（ATP结合）位点来破坏ILK活性，从而导致蛋白质降解。在强大的初步数据的启发下，我设计了一种策略，主要基于通过小分子结构破坏剂阻断这些关键相互作用伙伴的结合来促进ILK-Pinch-Parvin（IPP）复合物的降解。基于一个确定的命中支架，我将结合联合收割机两个配体和结构为基础的（在硅片上）药物设计，集中化学库合成和表型筛选在迭代的方式，与目标偏向药物样化合物，引发IPP复合物降解和GBM干细胞的抗增殖活性的化学发现。在设计、合成和表型筛选的几次迭代之后，将对有前景的化合物进行高级表型筛选和DMPK研究以产生最佳候选物。最后，我将通过共结晶探索最佳抑制剂的作用模式，并在GBM异种移植模型中评价最佳抑制剂的体内抗癌功效。通过发现新的小分子ILK降解剂，我雄心勃勃的项目旨在为GBM的治疗提供新的范式和策略。

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in adults, which is essentially incurable with median survival of about 12-18 months from diagnosis. There is an urgent need to identify and validate new molecular targets that reveal common biological vulnerabilities across GBM sub-types, and to devise novel therapeutic strategies. Integrin-linked kinase (ILK), an enigmatic pseudo-kinase downstream of integrins, drives the malignant GBM and acts as a potentially valuable target. Although undruggable ILK lacks catalytic activity, Prof Unciti-Broceta and Prof Frame have identified a novel chemical strategy to disrupt ILK activity by targeting its pseudo-kinase (ATP binding) site, which leads to protein degradation. Inspired in the strong preliminary data, I have devised a strategy based largely on promoting degradation of the ILK-Pinch-Parvin (IPP) complex by blocking the binding of these key interacting partners via small molecule structural disruptors. Based on an identified hit scaffold, I will combine both ligand and structure-based (in silico) drug design, focused chemical library synthesis and phenotypic screening in an iterative manner, with the goal to bias chemical discovery towards drug-like compounds that elicit IPP complex degradation and antiproliferative activities in GBM stem cells. After several iterations of design, synthesis and phenotypic screening, promising compounds will be carried out advanced phenotypic screening and DMPK studies to generate best candidate/s. Finally, I will explore the mode of action of best inhibitor/s by co-crystallization and evaluate in vivo anticancer efficacy of best inhibitor/s in GBM xenograft models. Through the discovery of novel small molecule ILK degraders, my ambitious project aims to provide a new paradigm and strategy for the treatment of GBM.