Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
J Med Chem. 2022 May 26;65(10):7231-7245. doi: 10.1021/acs.jmedchem.2c00185. Epub 2022 May 6.
MAGE proteins are cancer testis antigens (CTAs) that are characterized by highly conserved MAGE homology domains (MHDs) and are increasingly being found to play pivotal roles in promoting aggressive cancer types. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis (TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancer cells to chemotherapeutics like platinating agents. We use an mRNA display of thioether cyclized peptides to identify a series of potent and highly selective macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Co-crystal structure indicates that these inhibitors bind in a pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structural insights for the future development of MAGE-A4-targeted cellular probes.
MAGE 蛋白是癌症睾丸抗原（CTA），其特征是高度保守的 MAGE 同源结构域（MHD），并且越来越多地被发现在促进侵袭性癌症类型中发挥关键作用。特别是 MAGE-A4 通过稳定 E3 连接酶 RAD18 并促进跨损伤合成（TLS），增加了多种癌症中的 DNA 损伤耐受性和化学抗性。抑制 MAGE-A4：RAD18 轴可以使癌细胞对顺铂类化疗药物敏感。我们使用硫醚环肽的 mRNA 显示来鉴定一系列针对 MAGE-A4：RAD18 相互作用的有效且高度选择性的大环抑制剂。共晶结构表明，这些抑制剂结合在一个在 MHD 中保守的口袋中，但利用 A4 特异性残基来实现高同工型选择性。总的来说，我们的数据代表了第一个报道的 MAGE-A4：RAD18 相互作用抑制剂，并为未来开发针对 MAGE-A4 的细胞探针建立了生化工具和结构见解。
