基于3,5-二芳基-4,5-二氢吡唑骨架的BRAF/PI3K双靶点抑制剂的设计、合成与生物活性评价

Most patients with BRAF-mutant tumors develop resistance to selective RAF kinase inhibitors. Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/Akt/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. In some cases of resistance, the BRAF inhibitor continues to block the ERK pathway, but the cell seems to develop resistance through activation of PI3K. These results indicate that simultaneously inhibition of BRAF and PI3K is a promising therapeutic strategy for clinical BRAF inhibitor resistance.In this research, based on the leading 3,5-diaryl-4,5-dihydro-pyrazole skeleton we discovered as selective BRAF inhibitor, we focus on the identification and modification of novel BRAF/PI3K dual inhibitor. The leading compounds were obtained through in silico screening of compound library and in vitro evaluation of protein-kinase inhibitory activities. Structural optimization of leading compounds will be guided by the cross-over study of computer aided drug design (CADD), structure-activity relationship (SAR) and binding mode of target active compounds. Through preliminary druggability evaluation of pharmacological and toxicological assays, 1-2 hits with high efficiency and low toxicity are expected to be developed as anticancer candidates which could overcome clinical BRAF inhibitor resistance.

针对BRAF（B-RAF）抑制剂作为靶向抗肿瘤药物在临床使用过程中面临的耐药性难题，基于PI3K（磷脂酰肌醇-3-激酶，phosphoinositide 3-kinase）在BRAF抑制剂耐药性产生过程中的重要作用及两者在肿瘤发生发展过程之中广泛的交叉作用，使得开发针对BRAF/PI3K的双靶点抑制剂用于抗肿瘤药物极有可能在克服耐药性方面取得积极进展。本课题从前期工作中发现的新型具有3,5-二芳基-4,5-二氢吡唑结构的高效BRAF抑制剂骨架出发，结合基于靶标结构的药物分子合理设计，通过活性评价及时反馈深入探讨构效关系，经筛选、结构优化期望可以得到1-2个新型高效BRAF/PI3K双靶点抑制剂用于抗肿瘤候选药物，克服现有BRAF抑制剂在临床使用中出现的耐受性难题。

在50%的转移性黑色素瘤患者中都发现了因BRAF突变而导致MAPK通路的过度活化。自2011年开始BRAF抑制剂获批上市，在BRAF突变型的黑色素瘤患者中表现出惊人的临床益处。不幸的是，治疗效果通常是暂时的，患者在1年内会获得耐药性。研究证明PI3K参与的信号通路在BRAF抑制剂耐药性产生过程中发挥了重要作用。本课题从前期工作中发现的新型具有3,5-二芳基-4,5-二氢吡唑结构的高效BRAF抑制剂骨架出发，开发新型高效BRAF/PI3K双靶点抑制剂尝试用于解决BRAF抑制剂在临床使用中出现的耐受性难题。经筛选、结构优化得到二氢吡唑喹喔啉酰胺化合物BPL_14和二氢吡唑磺胺类化合物BPS_27，是具有良好临床应用前景的抗肿瘤候选药物，值得进一步研究开发作为克服BRAF抑制剂耐药性难题的新解决策略。