From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
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DOI：
10.1021/acs.jmedchem.9b00455
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发表时间：
2019-06-13
影响因子：
7.3
通讯作者：
Derksen, Darren J.
中科院分区：
文献类型：
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作者：
Papatzimas, James W.;Gorobets, Evgueni;Derksen, Darren J.
蛋白质-蛋白质相互作用（PPI）已成为治疗发展的重要目标，由于其在不同的生物过程中的关键性质。理想的基于PPI的靶点是蛋白质髓细胞白血病1（MCL 1），这是多发性骨髓瘤等癌症中的关键促生存因子，其中MCL 1水平与疾病进展直接相关。目前的策略，停止抗凋亡特性的MCL 1围绕抑制其隔离的促凋亡因子。现有的抑制剂破坏内源性调节蛋白;然而，这种策略实际上导致MCL 1蛋白水平的增加。在这里，我们展示了能够使用蛋白水解靶向嵌合体（PROTAC）方法选择性靶向MCL 1的异双功能小分子的开发，从而导致成功降解。我们已经证实了E3连接酶CUL 4A-DDB 1 cereblon泛素化途径的参与，使这些PROTAC成为一类新的抗凋亡B细胞淋巴瘤2家族蛋白降解剂的第一步。
Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.