逆转非小细胞肺癌EGFR-TKI耐药的新型PI3Kα/BET双靶点抑制剂的设计合成及其作用机制研究

Lung cancer is one of the malignant tumors with the highest morbidity and mortality all over the world. The approve of EGFR-TKI brings significant benefit for lung cancer patients with EGFR mutation. However, EGFR-TKI resistance becomes the biggest obstacle to its clinical application. Therefore, the development of novel drugs with high efficiency and low toxicity to overcome EGFR-TKI-induced drug resistance has become an urgent problem to be solved in the clinical treatment of lung cancer. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and activations of bypass or downstream signaling PI3K/Akt pathway. BET is associated with transcription and expression of various RTKs and the activation of downstream PI3K/Akt signaling pathways. Recent studies show concurrent inhibition of BET and PI3K signaling pathways can overcome EGFR-TKI resistance. In our previous study, we designed and synthesized a series of (2(3)-substituted-3,4- dihydroquinazolin-6-yl) imidazo[1,2-a] pyridine derivatives and found POQO-1, a novel dual inhibitor of BET/PI3Kα. Preliminary activity tests showed that PIQO-1 effectively reversed EGFR-TKI resistance in non-small cell lung cancer. On this basis, this project intends to design and synthesize a series of POQO-1 derivatives, evaluate the antitumor activity and elucidate the underlying mechanism, finally define the structure-effect relationship of these derivatives. It provides a theoretical basis for the further discovery of novel antitumor candidate drugs dual targeting BET and PI3Kα, as well as the application of these compounds in the reversal of EGFR-TKI resistance.

肺癌是全球发病率和死亡率最高的癌症，EGFR突变是肺癌最常见、也是获批靶向药物最多的突变靶点。EGFR-TKI的上市给肺癌患者带来了希望，但TKI耐药却成为限制其临床应用的最大障碍。因此发现高效低毒的新型药物以克服EGFR-TKI耐药成为了目前肺癌治疗中亟待解决的难题。EGFR耐药性突变、旁路RTKs及下游PI3K信号通路的活化是导致EGFR-TKI耐药的主要原因。BET参与调控多种RTKs的转录与表达，因此同时抑制BET和PI3K信号通路有望克服多种TKI的耐药。申请者前期设计合成了1个新型的PI3Kα/BET双靶点抑制剂PIQO-1，初步的活性研究发现PIQO-1能够有效地逆转非小细胞肺癌对EGFR-TKI耐药。本项目拟在此基础上，结合计算机辅助药物设计，对PIQO-1进行结构修饰，研究其抗癌活性与作用机制，明确其构效关系，为发现新型的PI3Kα/BET双靶向的肺癌治疗药物奠定基础。

肺癌是全球发病率和死亡率最高的癌症，EGFR（表皮生长因子受体）突变是肺癌最常见、也是获批靶向药物最多的突变靶点。EGFR-TKI的上市给众多肺癌患者带来了希望，在非小细胞肺癌的治疗中取得了显著的疗效。然而EGFR-TKI的耐药却成为了限制其临床疗效的瓶颈和最大挑战。因此，根据EGFR-TKI的耐药机制，制定相应的治疗策略，研发高效、低毒的新型抗癌药物以延缓或克服EGFR-TKI诱导的耐药、实现疗效的最大化成为了目前肺癌治疗中亟待解决的临床难题。研究表明，EGFR耐药性突变、旁路RTKs及下游PI3K信号通路等的活化是导致EGFR-TKI耐药的主要原因。BET参与调控多种RTKs的转录与表达，因此同时抑制BET和PI3K信号通路有望克服多种TKI的耐药。在前期研究中，我们发现了1个新型的PI3Kα/BET双靶点抑制剂PIQO-1，初步的活性研究发现PIQO-1能够有效地克服非小细胞肺癌对多种EGFR-TKI的耐药。本项目结合计算机辅助药物设计技术与药物化学合成方法，对PIQO-1进行结构修饰，通过骨架跃迁和药效团联合策略共设计合成了四类PIQO-1的衍生物，包括6-(2-取代-1H-苯[d]咪唑-6-基)喹唑啉-4(3H)-酮类衍生物（53个化合物），6-(2-取代咪唑[1,2-a]吡啶-6-基)喹唑啉-4(3H)-酮类衍生物（37个化合物）、6-(吡啶-3-基)喹唑啉-4(3H)-酮类衍生物（14个化合物）以及氨基苯并咪唑苯甲酰胺类衍生物（36个化合物），并对其开展了抗肿瘤及克服NSCLC对EGFR-TKI耐药的活性研究，获得了确切的构效关系。在该项目的支持下，我们发现了靶向两个或多个与EGFR-TKI耐药密切相关的靶点如PI3K、c-Met、BRD4、ROR1或Aurora kinase等的多靶向的先导化合物4个，为发现新型的多靶向的肺癌治疗药物奠定了基础。