Discovery and Structural Basis of the Selectivity of Potent Cyclic Peptide Inhibitors of MAGE-A4.
Discovery and Structural Basis of the Selectivity of Potent Cyclic Peptide Inhibitors of MAGE-A4.
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MAGE-A4强效环肽抑制剂选择性的发现和结构基础。
DOI：
10.1021/acs.jmedchem.2c00185
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发表时间：
2022-05-26
影响因子：
7.3
通讯作者：
Bowers AA
中科院分区：
文献类型：
--
作者：
Fleming MC;Chiou LF;Tumbale PP;Droby GN;Lim J;Norris-Drouin JL;Williams JG;Pearce KH;Williams RS;Vaziri C;Bowers AA
法师蛋白是众所周知的癌症睾丸抗原（CTA），其在癌症和生殖细胞中选择性表达。MAGE以高度保守的法师同源结构域（MHD）为特征，越来越多地报道MAGE在促进和维持侵袭性癌症类型中起关键作用。人们怀疑靶向MAGE将导致新的癌症特异性治疗。特别是MAGE-A4通过稳定E3-连接酶RAD 18从而促进跨损伤合成（TLS）来增加多种癌症中的DNA损伤耐受性和化学抗性。因此，MAGE-A4：RAD 18轴的抑制可以减弱DNA损伤反应并使癌细胞对化疗剂如铂化剂敏感。然而，目前还没有这种相互作用的已知抑制剂，有限的结构信息使得选择性MAGE-A4抑制剂的设计具有挑战性。我们使用硫醚环化肽的mRNA展示来鉴定MAGE-A4：RAD 18相互作用的一系列大环抑制剂。我们的先导大环化合物MTP-1的体外IC 50为21 nM，对MAGE-A4的选择性高于其他法师A家族成员。共晶体结构显示线性MTP-1结合在跨MHD保守的口袋中，但利用A4特异性残基来实现高同种型选择性。MTP-1的结合模式也有助于部分阐明RAD 18识别的机制。我们利用MTP-1的有效选择性在基于裂解物的ELISA测定中特异性检测MAGE-A4。累积起来，我们的数据代表了MAGE-A4：RAD 18相互作用的第一个报道的抑制剂，并为MAGE-A4靶向细胞探针的未来开发建立了生物化学工具和结构见解。
MAGE proteins are well-known cancer testis antigens (CTAs) that are selectively expressed in cancer and germline cells. Characterized by the highly conserved MAGE homology domain (MHD), MAGEs are increasingly reported to play pivotal roles in promoting and sustaining aggressive cancer types. It is suspected that targeting MAGEs will lead to new cancer specific therapeutics. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and thereby promoting trans-lesion synthesis (TLS). Accordingly, inhibition of the MAGE-A4:RAD18 axis could attenuate the DNA damage response and sensitize cancer cells to chemotherapeutics like platinating agents. However, there are currently no known inhibitors of this interaction and limited structural information makes the design of selective MAGE-A4 inhibitors challenging. We use mRNA display of thioether cyclized peptides to identify a series of macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Our lead macrocycle, MTP-1 exhibits an in vitro IC50 of 21nM and is highly selective for MAGE-A4 over other MAGE A-family members. A co-crystal structure shows that linear MTP-1 binds in a pocket that is conserved across MHDs but takes advantage of A4-specific residues to achieve high isoform selectivity. The binding mode of MTP-1 also helps to elucidate in part, the mechanism of RAD18 recognition. We exploit the potent selectivity of MTP-1 to specifically detect MAGE-A4 in lysate-based ELISA assays. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establishes biochemical tools and structural insights for the future development of MAGE-A4 targeted cellular probes.
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影响因子：
16.6
作者：
Gao Y;Mutter-Rottmayer E;Greenwalt AM;Goldfarb D;Yan F;Yang Y;Martinez-Chacin RC;Pearce KH;Tateishi S;Major MB;Vaziri C
通讯作者：
Vaziri C
影响因子：
11.2
作者：
Peikert, T;Specks, U;Comhair, SAA
通讯作者：
Comhair, SAA
RAD18 传递 DNA 损伤信号以引发同源重组修复。
影响因子：
21.3
作者：
Huang, Jun;Huen, Michael S. Y.;Kim, Hongtae;Leung, Charles Chung Yun;Glover, J. N. Mark;Yu, Xiaochun;Chen, Junjie
通讯作者：
Chen, Junjie
影响因子：
12.4
作者：
Hedglin M;Benkovic SJ
通讯作者：
Benkovic SJ
影响因子：
16
作者：
Doyle JM;Gao J;Wang J;Yang M;Potts PR
通讯作者：
Potts PR