以磷酸甘油酸酯激酶 pgk-1为靶点的新型活性小分子研究

Phosphoglycerate kinase-1 (pgk-1) is a kinase ubiquitously distributed in nearly all organisms, catalyzing key biochemical reactions in the glycolytic pathway. Recently research developments have identified that, besides glycolysis, pgk-1 also participates in many other signaling pathways and exhibits various important biological functions in cells. As a result, pgk-1 has been intimately implicated in many human diseases including neuropathy, malignant cancer, stroke, sepsis, infectious diseases, etc. As a classic kinase in glucose metabolism, pgk-1’s biochemical and structural properties have been extensively studied; however, research on pgk-1’s non-metabolic functions is still very limited, presumably due to the lack of effective small molecule probes that can modulate pgk-1’s enzymatic activities. Previously we discovered that terazosin, a marketed anti-hypertension drug, can activate pgk-1, and we have elucidated the underlying mechanism that pgk-1 activates the downstream HSP90 and then induce multi-stress resistance to apoptosis in cells and in vivo. Based on these results, here we propose to design and develop novel small molecules that can selectively activates and inhibits pgk-1, and to use these small molecules as probes to investigate the molecular mechanisms underlying pgk-1’s biological functions. We expect the proposed research will provide novel and useful tools for studying pgk-1, discovering drug candidates, and developing versatile probes targeting pgk-1 in various forms of cancers.

磷酸甘油酯激酶pgk-1是一种广泛存在于细胞内，在糖代谢中产生催化活性的重要激酶。除糖代谢之外，pgk-1还具有多种重要的生物功能：pgk-1的失调和神经系统疾病、恶性肿瘤、败血症、传染性疾病等人类重要疾病密切相关。虽然pgk-1的传统生物化学研究较为成熟，但由于缺乏有效的小分子探针，人们对pgk-1在糖代谢之外生物功能的研究和作用机制的理解非常有限，成为亟待取得突破的研究方向。我们的前期工作发现了pgk-1的小分子激活剂特拉唑嗪，并揭示了pgk-1激活下游的热受激蛋白HSP90，在细胞和活体中抑制凋亡的信号通路。本项目将基于该工作基础，以特拉唑嗪为出发点，发展新型骨架结构的活性小分子，实现对pgk-1的有效激活和抑制，并以此为探针工具进行pgk-1在肿瘤细胞中功能机制的研究。由于pgk-1在生命过程中的重要性，本申请对探索癌症分子机理、抗肿瘤药物研发方面，具有重要的科学和实际意义。

磷酸甘油酯激酶pgk-1是一种广泛存在于细胞内，在糖代谢中产生催化活性的重要激酶。除糖代谢之外，pgk-1还具有多种重要的生物功能：pgk-1的失调和神经系统疾病、恶性肿瘤、败血症、传染性疾病等人类重要疾病密切相关。虽然pgk-1的传统生物化学研究较为成熟，但对pgk-1在糖代谢之外生物功能的研究和作用机制的理解非常有限，成为亟待取得突破的研究方向。我们的前期工作发现了pgk-1的小分子激活剂特拉唑嗪，以及与下游热受激蛋白HSP90之间的关联。本项目基于该工作基础，以特拉唑嗪为化学基础，设计、合成，并发展了新型结构的pgk-1激活剂和抑制剂，并且在研究工作中发现了pgk-1与细胞中ISOC蛋白相关，存在新颖的ISOC-pgk-1蛋白复合体，在细胞迁移和细胞自噬的信号传导通路中起着重要作用。由于ISOC本身的蛋白结构和生物功能基本是空白，以及pgk-1在生命过程中的重要性，本项目的研究成果对探索癌症分子机理、抗肿瘤药物研发方面，提供了新颖的靶点以及药物开放的物质基础。