基于DNA编码分子库的BET-BD1与CBP/p300溴结构域双重抑制剂研究

溴结构域和超末端结构域（BET）蛋白是癌症治疗中重要的表观遗传靶点。目前有多个泛BET抑制剂进入了临床研究，然而泛BET抑制剂在临床试验中出现严重的在靶毒性（例如血小板减少）和耐药性。为克服泛BET抑制剂的上述问题，本项目计划发展BET-BD1与CBP/p300溴结构域双重抑制剂。该双重抑制剂能选择性抑制BET蛋白BD1溴结构域，降低泛BET抑制剂在靶毒性；通过抑制CBP/p300溴结构域达到协同药理效应，减少BET单靶点导致的耐药性。本项目利用反向化学遗传学技术——DNA编码分子库，结合申请人前期针对泛BET抑制剂的研究基础，设计并合成基于优势骨架的DNA编码聚焦分子库；通过靶蛋白对分子库进行筛选，获得选择性配体；通过结构优化、体内外生物学活性和成药性研究，期望发展出具有高抗癌活性、低毒性的BET-BD1和CBP/p300溴结构域双重抑制剂，为解决泛BET抑制剂出现的临床问题提供新途径。

Bromodomain and extra-terminal domains (BET) proteins feature as a key epigenetic target in cancer. There are currently plenty of pan-BET inhibitors under clinical investigation. Nevertheless, emerging severe on-target toxicity (like thrombocytopenia) and drug resistance hindered further development of pan-BET inhibitors. To solve obstacles above, this project innovatively aims to develop BET-BD1 and CBP/p300 dual inhibitors. This kind of inhibitors selectively inhibit BET-BD1 bromodomain for diminishing on-target toxicity; Meanwhile, Inhibition of CBP/p300 bromodomain would boost synergistic anti-cancer activity, leading to reduction in drug resistance. In this project, based on our previous research of pan-BET inhibitors, we design and synthesize a DNA-encoded focused library containing privileged scaffold using novel reverse chemical genetics technique “DNA-encoded library”. The library will be screened against targeted proteins in parallel to generate selective ligands, which would undergo further structural optimization and biological evaluation in vitro and in vivo. Eventfully this project would generate promising BET-BD1 and CBP/p300 bromodomain dual inhibitors with high anti-cancer potency and low toxicity, facilitating broaden clinical use of pan-inhibitors.