Development of Small Molecule degraders of ILK for glioblastoma therapy

多形性胶质母细胞瘤(GBM)是成人最常见和最具侵袭性的原发恶性脑肿瘤，确诊后中位生存期为12-18个月，基本上无法治愈。迫切需要确定和验证新的分子靶点，揭示不同GBM亚型的共同生物脆弱性，并设计新的治疗策略。整合素连接的激酶(ILK)是整合素下游的一种神秘的假性激酶，它驱动恶性的基底膜，是一个潜在的有价值的靶点。尽管无法用药的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)位点来干扰ILK的活性，从而导致蛋白质降解。受到强劲的初步数据的启发，我制定了一项策略，主要基于通过小分子结构干扰物阻止这些关键相互作用伙伴的结合来促进ilk-Pinch-Parvin(IPP)复合体的降解。基于已确定的HIT支架，我将结合配体和基于结构(在硅胶中)的药物设计，以迭代的方式集中化学库合成和表型筛选，目标是将化学发现偏向于导致GBM干细胞中IPP复合体降解和抗增殖活性的类药物化合物。经过几次迭代的设计、合成和表型筛选，有希望的化合物将进行高级表型筛选和DMPK研究，以产生最佳候选者/S。最后，我将探索最佳抑制剂/S的共结晶作用模式，并在体内评价最佳抑制剂/S在GBM异种移植模型中的抗癌效果。通过发现新的小分子同类降解剂，我雄心勃勃的项目旨在为GBM的治疗提供一种新的范式和策略。

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.