Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism.
Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism.
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Hec1（在癌症中高度表达1）或Nek2（NIMA相关激酶2）通常在预后不良的癌症中过表达。两者都是重要的有丝分裂调节因子，Nek2对Hec1 S165的磷酸化是正确的染色体分离所必需的。因此，通过靶向Hec1和Nek2与小分子的相互作用来灭活它们是解决这些类型癌症的理想策略。在这里，我们发现INH的新衍生物（Nek2和Hec1结合抑制剂）在W395，L399和K400残基上的氨基酸394 - 408处与Hec1结合，有效地阻断了S165上的Hec1被Nek2磷酸化，并在纳摩尔范围内杀死癌细胞。在机制上，Nek2的D-box（破坏盒）区在紧邻INH结合基序的氨基酸408 - 422处特异性结合Hec1。随后Nek2与INH结合的Hec1的结合触发了蛋白酶体介导的Nek2降解，而Hec1结合缺陷的Nek2突变体Nek2 R361L抵抗INH诱导的Nek2降解。这一发现揭示了一种新的药物作用机制，其中INH与Hec1的结合形成了一个虚拟的死亡陷阱，引发Nek 2降解并最终导致细胞死亡。此外，对乳腺癌患者样本的基因表达谱的分析显示，Hec1和Nek2的共同升高的表达与最短的生存期相关。用INH治疗患有这种肿瘤的小鼠显著抑制肿瘤生长，而没有明显的毒性。综上所述，新的INH衍生物适合转化为临床应用。
Hec1 (Highly Expressed in Cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here, we showed that new derivatives of INH (Inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394–408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408–422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.
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DOI：
10.1038/nrm3494
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
9
作者：
通讯作者：
--
影响因子：
5.1
作者：
Gurzov, EN;Izquierdo, M
通讯作者：
Izquierdo, M
影响因子：
11.2
作者：
Hayward, DG;Clarke, RB;Fry, AM
通讯作者：
Fry, AM