CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition
CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition
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DOI：
10.1210/en.2018-00083
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发表时间：
2018-09-01
期刊：
影响因子：
4.8
通讯作者：
Annes, Justin P.
中科院分区：
文献类型：
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作者：
Abdolazimi, Yassan;Zhao, Zhengshan;Annes, Justin P.
内源性β细胞的药理学扩增是治疗糖尿病的一种很有前途的策略。为了阐明控制β细胞生长的分子途径，我们筛选了2400个类似于大鼠β细胞复制调节活性的生物活性化合物。许多热门化合物损害或促进大鼠的β细胞复制，包括CC-401，这是一种高级临床候选药物，以前被描述为c-Junn末端激酶抑制物。令人惊讶的是，CC-401通过双特异性酪氨酸磷酸化调节激酶(Dyrk)1A和1B抑制诱导啮齿动物(体外和体内)和人类(体外)β细胞复制。与对复合治疗有广泛反应的大鼠β细胞不同，人β细胞的复制只被DYRK1A/B抑制剂始终如一地诱导。同时抑制糖原合成酶-3-β(GSK-3-β)或激活素A受体II-样激酶/转化生长因子-β(Alk5/转化生长因子-β)可增强这种作用。先前的工作强调DYRK1A/B依赖抑制激活T细胞核因子(NFAT)的激活是诱导人β细胞复制的主要机制。然而，抑制NFAT活性对CC-401诱导的β细胞复制的影响有限。因此，我们研究了CC-401依赖的DYRK1A/B抑制的额外作用。事实上，CC-401抑制了依赖DYRK1A的β细胞复制抑制物p27Kip1的磷酸化/稳定化。此外，CC-401增加了许多复制促进基因的表达，这些基因通常被二聚化伙伴、RB样蛋白、E2F和多外阴B类(DREAM)复合体抑制，该复合体依赖于DYRK1A/B的完整性，包括MYBL2和FOXM1。总之，我们提供了一个化合物概要，作为操纵控制β细胞复制的信号通路的有价值的资源，并利用DYRK1A/B抑制剂(CC-401)来扩大我们对控制β细胞生长的分子途径的理解。
Pharmacologic expansion of endogenous beta cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control beta-cell growthwe screened similar to 2400 bioactive compounds for rat beta-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat beta-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-JunN-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) beta-cell replication via dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat beta cells, which were broadly growth responsive to compound treatment, human beta-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3 beta (GSK-3 beta) or activin A receptor type II-like kinase/transforming growth factor-beta (ALK5/TGF-beta) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human beta-cell-replication induction. However, inhibitionofNFATactivity hadlimited effectonCC-401-induced beta-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the beta-cell-replication inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control beta-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of themolecular pathways that control beta-cell growth.