Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands.
Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands.
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DOI：
10.1111/cas.13284
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发表时间：
2017-08
期刊：
影响因子：
5.7
通讯作者：
Naito M
中科院分区：
文献类型：
--
作者：
Shibata N;Miyamoto N;Nagai K;Shimokawa K;Sameshima T;Ohoka N;Hattori T;Imaeda Y;Nara H;Cho N;Naito M
在某些癌细胞中发生染色体易位，这导致包括慢性髓细胞性白血病（CML）中BCR-ABL在内的异常致癌融合蛋白的表达。ABL酪氨酸激酶抑制剂，如伊马替尼和达沙替尼，表现出显着的治疗效果，虽然耐药性的出现阻碍了长期治疗的治疗。治疗CML的另一种方法是下调BCR-ABL蛋白。我们设计了一种名为特异性和非遗传性凋亡蛋白抑制剂依赖性蛋白擦除器（Specific and Non‐genetic inhibitor of apoptosis protein [IAP]‐dependent Protein Erasers，SNIPER）的杂合分子敲除系统，旨在诱导IAP介导的靶蛋白泛素化和蛋白酶体降解，最近开发了一对针对BCR‐ABL蛋白的SNIPER（ABL）。在这项研究中，我们测试了ABL抑制剂和IAP配体的各种组合，并针对SNIPER（ABL）的蛋白质敲低活性优化了接头。得到的SNIPER（ABL）-39，其中达沙替尼通过聚乙二醇（PEG）× 3接头与IAP配体LCL 161衍生物缀合，显示出降解BCR-ABL蛋白的有效活性。机制分析表明，细胞凋亡抑制蛋白1（cIAP 1）和X连锁凋亡抑制蛋白（XIAP）在BCR‐ABL蛋白降解中起作用。与BCR-ABL蛋白的降解一致，SNIPER（ABL）-39抑制信号转导和转录激活因子5（STAT 5）和Crk样原癌基因（CrkL）的磷酸化，并抑制BCR-ABL阳性CML细胞的生长。这些结果表明，SNIPER（ABL）-39可能是针对BCR-ABL-阳性CML的基于降解的新型抗癌药物的候选者。
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR‐ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long‐term treatment. An alternative approach to treat CML is to downregulate the BCR‐ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non‐genetic inhibitor of apoptosis protein [IAP]‐dependent Protein Erasers (SNIPER), which is designed to induce IAP‐mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR‐ABL protein have been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)‐39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR‐ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X‐linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR‐ABL protein. Consistent with the degradation of BCR‐ABL protein, the SNIPER(ABL)‐39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto‐oncogene (CrkL), and suppressed the growth of BCR‐ABL‐positive CML cells. These results suggest that SNIPER(ABL)‐39 could be a candidate for a degradation‐based novel anti‐cancer drug against BCR‐ABL‐positive CML.
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影响因子：
64.8
作者：
HEISTERKAMP, N;STAM, K;GROSVELD, G
通讯作者：
GROSVELD, G
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
影响因子：
5.7
作者：
Ohoka N;Nagai K;Shibata N;Hattori T;Nara H;Cho N;Naito M
通讯作者：
Naito M
影响因子：
64.8
作者：
ROWLEY, JD
通讯作者：
ROWLEY, JD
影响因子：
3.6
作者：
Puppala, Dinesh;Lee, Hyosung;Swanson, Hollie I.
通讯作者：
Swanson, Hollie I.