A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL.,ACS Chemical Biology

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A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-06-22 , DOI: 10.1021/acschembio.0c00348
Bingqi Tong _{1,

2} , Jessica N Spradlin _{1,

2} , Luiz F T Novaes _{1,

2} , Erika Zhang ₁ , Xirui Hu _{1,

2} , Malte Moeller _{1,

2} , Scott M Brittain _{2,

3} , Lynn M McGregor _{2,

3} , Jeffrey M McKenna _{2,

3} , John A Tallarico _{2,

3} , Markus Schirle _{2,

3} , Thomas J Maimone _{1,

2} , Daniel K Nomura _{1,

2,

4,

5,

6}

Affiliation

Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific proteins in a proteasome-dependent manner. However, a major limitation of TPD is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent recruiter for the E3 ligase RNF114. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or, in some cases, inactivity. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs, and we demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing selectivity for the degradation of neo-substrate proteins.

中文翻译：

一种基于Nimbolide的激酶降解剂可优先降解致癌BCR-ABL。

靶向蛋白降解（TPD）和靶向蛋白水解的嵌合体（PROTAC）已经成为以蛋白酶体依赖性方式降解特定蛋白的强大治疗手段。但是，TPD的主要局限性是缺乏E3连接酶募集者。最近，我们发现天然产物nimbolide作为E3连接酶RNF114的共价募集者。在这里，我们显示了nimbolide作为TPD应用中E3连接酶募集者的广泛用途。我们证明，与先前报道的大脑或VHL征募的BCR-ABL降解物相比，将nimbolide连接到激酶和BCR-ABL融合癌基因抑制剂dasatinib BT1的PROTAC有选择性地在白血病癌细胞中降解cCR-ABL的BCR-ABL。相反的选择性，或者在某些情况下是不活跃的。从而，

更新日期：2020-07-17

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