Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.

Popowicz GM; Wolf S; Wang W; Holak TA

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Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.

机译：与MDMX和MDM2结合的低分子量抑制剂的结构揭示了P53-MDMX / MDM2拮抗剂药物发现的新方法。

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Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.

机译：已经提出了密集的抗癌药物发现努力，用于开发P53-MDM2和P53-MDMX相互作用的小分子抑制剂。我们在此存在基于新的咪唑吲哚支架的MDM2和MDMX结合的最有效的抑制剂的结构。此外，描述了最近报道的螺氧吲哚抑制剂与MDM2结合的结构。该结构表示应如何优化与MDM2 / X-P53相互作用的三个子载体结合的小分子的取代物用于有效结合MDM2和/或MDMX。虽然螺氧吲哚抑制剂触发MDM2的显着配体诱导的变化，但咪唑吲哚份额为MDMX和MDM2份额相似，但仅导致两种蛋白质的结构中的最小诱导变化。我们的研究包括MDMX和小分子之间复合物的第一结构，并且应该有助于显影与MDMX和/或MDM2结合的有效支架。

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《Cell cycle》 |2010年第6期|共8页
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Popowicz GM; Wolf S; Wang W; Holak TA;
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Max Planck Institute for Biochemistry Martinsried Germany.;

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正文语种 eng
中图分类细胞生物学;
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1. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. [J] . Popowicz GM, Wolf S, Wang W, Cell cycle . 2010,第6期

机译：与MDMX和MDM2结合的低分子量抑制剂的结构揭示了p53-MDMX / MDM2拮抗剂药物发现的新方法。
2. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. [J] . Popowicz GM, Wolf S, Wang W, Cell cycle . 2010,第6期

机译：与MDMX和MDM2结合的低分子量抑制剂的结构揭示了P53-MDMX / MDM2拮抗剂药物发现的新方法。
3. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. [J] . Popowicz GM, Wolf S, Wang W, Cell cycle . 2010,第6期

机译：与MDMX和MDM2结合的低分子量抑制剂的结构揭示了P53-MDMX / MDM2拮抗剂药物发现的新方法。
4. Peptide-Guided Design of Mdm2/MdmX Inhibitors with Anticancer Activity [C] . Lingyun Qin, Yao Chen, Rong Chen American Peptide Symposium . 2015

机译：抗癌活动MDM2 / MDMX抑制剂的肽导向设计
5. Virtual Screening for Inhibitors of Anti-apoptotic Proteins: DCK, BCL-XL, MCL-1, MDMX, and MDM2 [D] . Du Boulay, Courtney Jerome 2013

机译：虚拟筛选抗凋亡蛋白抑制剂：DCK，BCL-XL，MCL-1，MDMX和MDM2
6. PNAS Plus: Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy [O] . Yong S. Chang, Bradford Graves, Vincent Guerlavais, 2013

机译：PNAS Plus：钉合α-螺旋肽药物开发：一种有效的MDM2和MDMX双重抑制剂用于依赖p53的癌症治疗
7. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery [O] . Grzegorz M. Popowicz, Anna Czarna, Siglinde Wolf, 2010

机译：结合MDMX和MDM2的低分子量抑制剂的结构揭示了P53-MDMX / MDM2拮抗剂药物发现的新方法

Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.

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