TCP衍生LSD1抑制剂的脱靶作用研究和先导化合物优化

While several known tranylcypromine (TCP)-derived LSD1 drugs displayed unexpected in vivo toxicity, TCP-derived LSD1 inhibitors found in this group showed good efficacy and toxicity profile on mouse xenograft model. Preliminary SAR and mechanism study failed to show reasonable connection among enzymatic activity, cellular activity, and in vivo efficacy/toxicity data. This issue became a major hurdle preventing the lead discovery and optimization of LSD1 inhibitors, and off-target interactions were considered the underlying reason. Thus, a project employing medicinal chemical biology approaches to characterize off-target behaviors of TCP derivatives was conceived. TCP-derived LSD1 inhibitors of good in vivo efficacy, structure diversity, and different toxicity profiles will be used to draw the correlations between target selectivity and toxicity. Consequently, a generalized structure activity relationship embodying selectivity, efficacy, and toxicity factors will be deduced. And a rational design and evaluation strategy for LSD1 inhibitor development will be formed. Guided by this strategy, further structure design, optimization, and evaluation will be carried out to ensure the discovery of high quality LSD1 inhibitor lead compounds for the future drug development.

申请人在前期研究中发现包括部分阳性药在内的苯基环丙胺（TCP）衍生LSD1抑制剂具有未见报道的，较高的小鼠体内毒性，又发现一些新型TCP衍生LSD1抑制剂具有较好的体内活性和较低的毒性。经过初步构效关系和分子机理研究，申请人发现：根据现有评价系统，无法在这些化合物的分子活性、细胞活性、体内药效/毒性之间建立合理的联系；且该问题已对LSD1抑制剂的先导化合物发现和优化构成了显著的障碍。申请人进一步认为该问题是由于TCP衍生LSD1抑制剂未知的脱靶作用所导致的。因此，申请人计划采用药物化学生物学研究手段，对一些具有较好药效，但具有不同结构或毒性特征的TCP衍生LSD1抑制剂进行脱靶作用研究；分析脱靶作用靶点与毒性之间的关联，建立多维的靶点选择性-活性-毒性构效关系，归纳并形成LSD1抑制剂的合理设计和筛选策略；并通过进一步结构优化和筛选，获得一批具有较高开发价值的LSD1抑制剂先导化合物。

赖氨酸特异性去甲基化酶 LSD1是新颖的表观遗传学抗肿瘤靶点，能够使H3K4和H3K9发生去甲基化，通过调控肿瘤相关基因的表达，促进肿瘤细胞的增殖、侵袭和转移。目前进入临床研究的化合物多为TCP类衍生物共价抑制剂。LSD1共价抑制剂由于脱靶作用而存在治疗安全窗较窄的问题。申请人基于前期研究基础，首先开展了共价抑制剂的研究工作，获得了数个体内外活性优于GSK2879552的化合物。同时申请人通过跟踪LSD1靶点研究前沿，又开展了非共价抑制剂的研究工作，开展了较为详细的构效关系研究工作，获得数个体内外活性较好的候选化合物，具有进一步开发的潜力。