Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.
Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.
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DOI：
10.1038/s41598-018-31913-5
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发表时间：
2018-09-10
影响因子：
4.6
通讯作者：
Naito M
中科院分区：
文献类型：
--
作者：
Shibata N;Shimokawa K;Nagai K;Ohoka N;Hattori T;Miyamoto N;Ujikawa O;Sameshima T;Nara H;Cho N;Naito M
慢性粒细胞性白血病（CML）的特征是致癌融合蛋白BCR-ABL蛋白激酶，针对该蛋白激酶已开发出临床上有用的抑制剂。治疗CML的另一种方法是降解BCR-ABL蛋白。最近，通过将达沙替尼与E3泛素连接酶的配体结合，开发了针对BCR-ABL的有效降解剂。由于降解物含有达沙替尼部分，它们还抑制BCR-ABL激酶活性，这使我们对降解物降解BCR-ABL对CML生长抑制的影响的理解变得复杂。为了解决这个问题，我们选择了DAS-IAP作为一种有效的BCR-ABL降解剂，并开发了一种结构相关的无活性降解剂DAS-meIAP，它抑制激酶活性，但不降解BCR-ABL蛋白。当处理CML细胞48 h时，DAS-IAP显示出比DAS-meIAP略弱的抑制细胞生长的活性。然而，即使在短期治疗后去除药物，DAS-IAP也显示出持续的生长抑制，而在去除DAS-meIAP和达沙替尼后，CML细胞生长迅速恢复。同样，在DAS-IAP去除后，BCR-ABL水平和下游激酶信号传导的抑制得以维持，而在DAS-meIAP和达沙替尼去除后，激酶信号传导迅速恢复。这些结果表明，BCR-ABL降解剂比ABL激酶抑制剂对CML细胞生长的抑制作用更持久。
Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit BCR-ABL kinase activity, which complicates our understanding of the impact of BCR-ABL degradation by degraders in CML growth inhibition. To address this issue, we chose DAS-IAP, as a potent BCR-ABL degrader, and developed a structurally related inactive degrader, DAS-meIAP, which inhibits kinase activity but does not degrade the BCR-ABL protein. DAS-IAP showed slightly weaker activity than DAS-meIAP in inhibiting cell growth when CML cells were treated for 48 h. However, DAS-IAP showed sustained growth inhibition even when the drug was removed after short-term treatment, whereas CML cell growth rapidly resumed following removal of DAS-meIAP and dasatinib. Consistently, suppression of BCR-ABL levels and downstream kinase signaling were maintained after DAS-IAP removal, whereas kinase signaling rapidly recovered following removal of DAS-meIAP and dasatinib. These results indicate that BCR-ABL degrader shows more sustained inhibition of CML cell growth than ABL kinase inhibitor.
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影响因子：
7.3
作者：
Chan KH;Zengerle M;Testa A;Ciulli A
通讯作者：
Ciulli A
影响因子：
64.8
作者：
HEISTERKAMP, N;STAM, K;GROSVELD, G
通讯作者：
GROSVELD, G
影响因子：
11.5
作者：
Brave, Michael;Goodman, Vicki;Pazdur, Richard
通讯作者：
Pazdur, Richard
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：
4
作者：
Buckley DL;Raina K;Darricarrere N;Hines J;Gustafson JL;Smith IE;Miah AH;Harling JD;Crews CM
通讯作者：
Crews CM