间变性淋巴瘤（ALK）激酶是非小细胞肺癌药物研发重要的分子靶标，然而现有的ALK抑制剂由于耐药严重制约其临床应用。点突变G1202R是现有ALK抑制剂难以克服的最顽固的耐药突变。因此，研究能克服G1202R突变的新型ALK抑制剂具有重要临床意义。针对突变后R1202的大位阻及电性作用迫使抑制剂不能与ALK激酶结合导致活性丧失，本课题组近期基于R1202的位阻及电性，对配体的临近结构区域进行多样性药化修饰，包括负电性基团引入、柔性链替换、取代基移位等，发现化合物SOMCL-15-665对ALK G1202R突变有效，IC50达到65.0 nM。本项目将基于现有抑制剂与ALKG1202R的对接信息，对先导物SOMCL-15-665进行多角度多参数优化，获得靶向ALKG1202R高活性抑制剂，并对活性化合物进行系统的体内外活性及成药研究，为进一步研发新一代ALK抑制剂奠定基础。

Tyrosine kinase ALK is an important molecular target for non-small cell lung cancer. The clinical use of current ALK inhibitors is limited by the occurrence of resistant mutations, especially the point mutation G1202R, which both the first and second generation ALK inhibitors failed to combat. Since G1202R mutation results in a positively charged, bulky arginine residue at this position that can cause severe atomic collisions with the ligand, our group has recently focused on the development of novel ALK inhibitors by targeting ALK G1202R mutant as well as a variety of other frequently observed mutants. Compound SOMCL-15-665 bearing a flexible amide chain with negative electricity was identified to potently inhibit ALK G1202R mutant with IC50 value of 65.0 nM. Based on this result, the current project is proposed to conduct a diverse medicinal chemistry modification by focusing on the ligand structure nearby the positively charged, bulky arginine residue. New compounds with high potency against ALK G1202R as well as a variety of other frequently observed mutations inhibitors are expected. These compounds will be further evaluated both in vitro and in vivo, which will serve as the basis for the development of new generation ALK inhibitors for clinical use.