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对蛋白激酶Akt共价变构抑制的结构与化学见解。

Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt.

作者信息

Uhlenbrock Niklas, Smith Steven, Weisner Jörn, Landel Ina, Lindemann Marius, Le Thien Anh, Hardick Julia, Gontla Rajesh, Scheinpflug Rebekka, Czodrowski Paul, Janning Petra, Depta Laura, Quambusch Lena, Müller Matthias P, Engels Bernd, Rauh Daniel

机构信息

Faculty of Chemistry and Chemical Biology , TU Dortmund University , Drug Discovery Hub Dortmund (DDHD) am Zentrum für integrierte Wirkstoffforschung (ZIW) , Otto-Hahn-Strasse 4a , 44227 Dortmund , Germany . Email:

Faculty for Chemistry and Pharmacy , Institut für Physikalische und Theoretische Chemie , Universität Würzburg , Emil-Fischer-Strasse 42 , 97074 Würzburg , Germany.

出版信息

Chem Sci. 2019 Feb 13;10(12):3573-3585. doi: 10.1039/c8sc05212c. eCollection 2019 Mar 28.

DOI:10.1039/c8sc05212c
PMID:30996949
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6430017/
Abstract

The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation, cell growth, and apoptosis, rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

摘要

丝氨酸/苏氨酸激酶Akt（蛋白激酶B/PKB）是细胞信号转导通路中的一个主控开关。其下游信号传导影响细胞增殖、细胞生长和细胞凋亡，使Akt成为一个重要的药物靶点。Akt独特的激活机制涉及其N端普列克底物蛋白同源性（PH）结构域和激酶结构域相对取向的改变，使得该激酶适合进行高度特异性的变构调节。在此，我们展示了一组与全长Akt复合的共价变构域间抑制剂的独特晶体结构，并报告了基于这些创新抑制剂的聚焦文库的结构设计、合成、生物学和药理学评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/a734308cbd5d/c8sc05212c-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/3ff7371c7456/c8sc05212c-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/b704aab0c4c6/c8sc05212c-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/9695984fca94/c8sc05212c-s2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/1187da39af72/c8sc05212c-s3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/62156ebc1753/c8sc05212c-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/c20d84999a1f/c8sc05212c-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/a734308cbd5d/c8sc05212c-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/3ff7371c7456/c8sc05212c-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/b704aab0c4c6/c8sc05212c-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/9695984fca94/c8sc05212c-s2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/1187da39af72/c8sc05212c-s3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/62156ebc1753/c8sc05212c-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/c20d84999a1f/c8sc05212c-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cd4/6430017/a734308cbd5d/c8sc05212c-f4.jpg

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