A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex.
A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex.
复制标题
DOI：
10.1016/j.chembiol.2021.02.007
复制
发表时间：
2021-08-19
影响因子：
8.6
通讯作者：
Kielkopf CL
中科院分区：
文献类型：
--
作者：
Chatrikhi R;Feeney CF;Pulvino MJ;Alachouzos G;MacRae AJ;Falls Z;Rai S;Brennessel WW;Jenkins JL;Walter MJ;Graubert TA;Samudrala R;Jurica MS;Frontier AJ;Kielkopf CL
失调的前 mRNA 剪接是癌症和骨髓增生异常的一个新的致命弱点。为了扩展目前有限的小分子药物先导化合物组合，我们筛选了 U2AF 复合物的化学调节剂，该复合物使剪接体组装成核并在骨髓增生异常中发生突变。命中化合物特异性增强 U2AF2 亚基的 RNA 结合。值得注意的是，该化合物抑制代表性底物的剪接，并在 U2AF 功能阶段阻止剪接体组装。计算对接以及结构引导诱变表明该化合物通过疏水性和静电部分桥接串联 U2AF2 RNA 识别基序。表达与癌症相关的 U2AF1 突变体的细胞会被该化合物优先杀死。总而言之，我们的结果强调了捕获早期剪接体组装作为操纵前 mRNA 剪接的有效药理学手段的潜力。通过扩展，我们认为稳定组装中间体可能为大分子机器的小分子抑制提供有用的方法。许多癌症和骨髓增生异常与前 mRNA 剪接缺陷有关。 Chatrikhi 等人描述了一种命中化合物，它通过与 U2AF2 结合并促进 U2AF2-RNA 缔合，在剪接体组装的初始阶段阻止前 mRNA 剪接。该分子的治疗会改变剪接并优先杀死表达癌症相关 U2AF1 突变体的细胞。
Dysregulated pre-mRNA splicing is an emerging Achilles’ heel of cancers and myelodysplasias. To expand the currently limited portfolio of small molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small molecule inhibition of macromolecular machines. Many cancers and myelodysplasias are associated with pre-mRNA splicing defects. Chatrikhi et al describe a hit compound that stalls pre-mRNA splicing at the initial stages of spliceosome assembly by binding to U2AF2 and promoting U2AF2-RNA association. Treatment with the molecule alters splicing and preferentially kills cells expressing a cancer-relevant U2AF1-mutant.
登录
查看更多内容
影响因子：
5.3
作者：
Agafonov, Dmitry E.;Deckert, Jochen;Luehrmann, Reinhard
通讯作者：
Luehrmann, Reinhard
影响因子：
3.4
作者：
Hong, D. S.;Kurzrock, R.;LoRusso, P.
通讯作者：
LoRusso, P.
影响因子：
4.8
作者：
Effenberger, Kerstin A.;Anderson, David D.;Jurica, Melissa S.
通讯作者：
Jurica, Melissa S.
影响因子：
5.3
作者：
Guth, S;Tange, TO;Valcárcel, J
通讯作者：
Valcárcel, J
影响因子：
16
作者：
Das, R;Zhou, ZL;Reed, R
通讯作者：
Reed, R