Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation.
Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation.
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DOI：
10.1038/s41467-021-26935-z
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发表时间：
2021-11-16
影响因子：
16.6
通讯作者：
Geyer M
中科院分区：
文献类型：
--
作者：
Kaltheuner IH;Anand K;Moecking J;Düster R;Wang J;Gray NS;Geyer M
同源结构域相互作用蛋白激酶（HIPKs）属于CMGC激酶家族，与双特异性酪氨酸磷酸化调节激酶（DYRKs）密切相关。HIPK是多种信号通路的调节剂，并参与癌症、慢性纤维化、糖尿病和多种神经退行性疾病的病理学。在这里，我们报告了HIPK 3在其载脂蛋白形式的晶体结构在2.5 μ m分辨率。重组HIPKs和DYRK 1A被自动激活并磷酸化负延伸因子SPT 5、转录因子c-Myc和RNA聚合酶II的C-末端结构域，这表明它们在转录调控中具有直接功能。基于数据库检索，我们确定abemaciclib是FDA批准的用于治疗转移性乳腺癌的Cdk 4/Cdk 6抑制剂，是HIPK 2、HIPK 3和DYRK 1A的有效抑制剂。我们确定了与abemaciclib结合的HIPK 3和DYRK 1A的晶体结构，显示出与Cdk 6观察到的激酶铰链区相似的结合模式。值得注意的是，bemaciclib在体外对DYRK 1A的抑制程度与Cdk 4/Cdk 6相同，这引发了一个问题，即靶向DYRK 1A是否有助于bemaciclib的转录抑制和治疗活性。Abemaciclib是第三代CDK导向药物，用于治疗HR + /HER 2阴性晚期或转移性乳腺癌。在本文中，作者证明了同源结构域相互作用蛋白激酶（HIPKs）HIPK 3和DYRK 1A的成员也是Abemaciclib的靶点。
Homeodomain-interacting protein kinases (HIPKs) belong to the CMGC kinase family and are closely related to dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). HIPKs are regulators of various signaling pathways and involved in the pathology of cancer, chronic fibrosis, diabetes, and multiple neurodegenerative diseases. Here, we report the crystal structure of HIPK3 in its apo form at 2.5 Å resolution. Recombinant HIPKs and DYRK1A are auto-activated and phosphorylate the negative elongation factor SPT5, the transcription factor c-Myc, and the C-terminal domain of RNA polymerase II, suggesting a direct function in transcriptional regulation. Based on a database search, we identified abemaciclib, an FDA-approved Cdk4/Cdk6 inhibitor used for the treatment of metastatic breast cancer, as potent inhibitor of HIPK2, HIPK3, and DYRK1A. We determined the crystal structures of HIPK3 and DYRK1A bound to abemaciclib, showing a similar binding mode to the hinge region of the kinase as observed for Cdk6. Remarkably, DYRK1A is inhibited by abemaciclib to the same extent as Cdk4/Cdk6 in vitro, raising the question of whether targeting of DYRK1A contributes to the transcriptional inhibition and therapeutic activity of abemaciclib. Abemaciclib is a third generation CDK-directed drug used in the treatment of HR + /HER2 negative advanced or metastatic breast cancer. Here the authors demonstrate that members of the Homeodomain-interacting protein kinases (HIPKs) HIPK3 and DYRK1A are also targeted by Abemaciclib.
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影响因子：
13.8
作者：
Bieniossek C;Imasaki T;Takagi Y;Berger I
通讯作者：
Berger I
DOI：
10.1186/1756-9966-31-63
发表时间：
2012-08-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
D'Orazi G;Rinaldo C;Soddu S
通讯作者：
Soddu S
影响因子：
16
作者：
Di Vona, Chiara;Bezdan, Daniela;de la Luna, Susana
通讯作者：
de la Luna, Susana
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
5.7
作者：
Chen, Ping;Lee, Nathan V.;Murray, Brion W.
通讯作者：
Murray, Brion W.