来那度胺活性的新机制。
The novel mechanism of lenalidomide activity.
作者信息
Fink Emma C, Ebert Benjamin L
机构信息
Brigham and Women's Hospital, Division of Hematology, Boston, MA.
出版信息
Blood. 2015 Nov 19;126(21):2366-9. doi: 10.1182/blood-2015-07-567958. Epub 2015 Oct 5.
Abstract
Lenalidomide acts by a novel drug mechanism-modulation of the substrate specificity of the CRL4(CRBN) E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and IKZF3 by CRL4(CRBN). Subsequent proteasomal degradation of these transcription factors kills multiple myeloma cells. In del(5q) myelodysplastic syndrome, lenalidomide induces the degradation of CK1α, which preferentially affects del(5q) cells because they express this gene at haploinsufficient levels. In the future, modulation of ubiquitin ligase function may enable us to target previously "undruggable" proteins.
摘要
来那度胺通过一种新型药物机制发挥作用——调节CRL4(CRBN) E3泛素连接酶的底物特异性。在多发性骨髓瘤中，来那度胺通过CRL4(CRBN)诱导IKZF1和IKZF3的泛素化。这些转录因子随后被蛋白酶体降解，从而杀死多发性骨髓瘤细胞。在伴有5号染色体长臂缺失（del(5q)）的骨髓增生异常综合征中，来那度胺诱导CK1α的降解，这对del(5q)细胞有优先影响，因为它们单倍体不足水平表达该基因。未来，泛素连接酶功能的调节可能使我们能够靶向以前“不可成药”的蛋白质。
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