精氨酸甲基转移酶家族（PRMTs）广泛参与包括表观遗传在内的多种生理过程，也是重要的抗肿瘤靶标。多种体内外小分子可调控PRMTs活性，因而具有重要生物学意义，如内源性代谢物对PRMTs的调控是营养环境通过代谢影响表观遗传的表现形式之一；而外源性PRMT抑制剂是肿瘤治疗的潜在手段。由于PRMTs包含9个具有不同生理功能的成员，因此系统评估小分子对不同PRMTs的选择性对阐明其分子作用机制至关重要。然而，使用纯化的PRMTs评估小分子选择性的体外生化方法忽略了生理环境中复杂因素的影响，而在细胞水平给药的表型实验难以直接测定抑制剂对靶标的亲和力。因此，本项目拟通过开发新型泛亲和探针对细胞裂解液中的PRMTs进行富集，进而利用蛋白质组学系统定量解析重要小分子在生理环境中对PRMTs的亲和力及选择性，为阐明内源性代谢物的新调控机制，发现已有抑制剂的新适应症，以及开发新型选择性抑制剂提供重要信息。

Protein arginine methyltransferases (PRMTs) widely participate in diverse biological processes including epigenetic regulation and represent important anti-tumor targets. Endogenous and exogenous small organic molecules can exert multifaceted biological or pathological functions by regulating PRMTs activities. For example, the regulation by endogenous metabolites is one of manifestations of nutrient environment affecting epigenetic regulation via metabolism, whereas exogenous PRMT inhibitors are potential therapeutic treatments for cancer. Since PRMTs comprise of 9 members with distinct biological functions, assessing the selectivity of these bioactive small molecules is essential to elucidate their mechanisms of action in cell. However, the in vitro biochemical assays employing purified recombinant PRMTs failed to take into account the influence of complex cellular milieu, while the cellular phenotypic assays are not able to directly evaluate the inhibitor-target affinity. Therefore, we seek to develop novel pan- affinity probes to enrich PRMTs in lysate, and establish a new competitive quantitative chemical proteomic platform to systematically elucidate the target PRMTs of important bioactive small molecules. This work will facilitate the delineation of new mechanism of action for endogenous metabolites, repurpose the existing PRMT inhibitors for new therapeutic strategy and provide important information for the development of new selective PRMTs inhibitors.