MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.
MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.
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DOI：
10.1158/0008-5472.can-18-2918
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发表时间：
2019-01-01
期刊：
影响因子：
11.2
通讯作者：
Crews CM
中科院分区：
文献类型：
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作者：
Hines J;Lartigue S;Dong H;Qian Y;Crews CM
虽然被PROTAC有效靶向翻译后降解的蛋白质的数量稳定增长，但成功用于实现这一目标的E3连接酶的数量仅限于已发现小分子配体的少数几种。尽管E3连接酶MDM2被nutlin类小分子配体结合，但几乎没有基于nutlin的PROTAC。由于基于nutlin的PROTAC应该既敲低其靶蛋白又上调肿瘤抑制因子p53，因此我们检查了这种PROTAC降低癌细胞活力的能力。基于nutlin的BRD4降解PROTAC A1874能够以纳摩尔效力将其靶蛋白降解98%。考虑到A1874稳定p53的互补能力，我们发现基于nutlin的PROTAC在抑制具有野生型p53的许多癌细胞系的增殖方面比相应的利用VHL的PROTAC更有效，其具有类似的降解BRD 4的效力和功效。这是第一次报告的PROTAC，其中E3连接酶配体和靶向弹头联合收割机组合发挥协同抗增殖作用。我们的研究强调了未开发的潜力，可以通过扩大可以由PROTAC招募的E3连接酶的库来解锁。
While the number of proteins effectively targeted for post-translational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small molecule ligands, there are few nutlin-based PROTAC. Since a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor, p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC.