从新型和选择性DEL打击中发现NSD2-降解剂
Jan LegaardAndersson1, Jesper Christensen2, Daniela Kleine-Kohlbrecher2
1Nuevolution A/S / Amgen Research Copenhagen, Rønnegade 8, 2100, Copenhagen, Denmark.
Chembiochem : a European journal of chemical biology
|October 9, 2023
概括
研究人员开发了针对NSD2蛋白的新型小分子,NSD2蛋白是某些癌症的关键驱动因素. 这些分子有效降解NSD2,减少致癌的甲基化标记,并抑制癌细胞生长.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- NSD2 (含蛋白2的核受体结合集域) 是一种基因素甲基转移酶.
- 异常NSD2活性,由突变或转位驱动,如t(4;14),是致癌的,并与诸如多发性髓瘤和急性淋巴细胞白血病等癌症有关.
- 具体来说,NSD2 E1099K突变体表现出过度活跃的甲基转移酶功能.
研究的目的:
- 识别和开发针对NSD2.2.的新型小分子.
- 研究NSD2降解在癌症治疗中的治疗潜力.
- 探讨NSD2抑制对基因素甲基化和癌细胞增殖的影响.
主要方法:
- 利用DNA编码的库来发现与NSD2 PWWP1域结合的小分子连接体.
- 开发了基于已识别的配体的选择性VHL1-招募降解剂.
- 评估NSD2降解剂在癌细胞系中的有效性,测量NSD2降解,H3K36me2水平和细胞增殖.
主要成果:
- 确定了与NSD2 PWWP1域结合的有力和选择性的小分子配体.
- 这些配体抑制NSD2与H3K36me2-核酶的相互作用,而不会影响其甲基转移酶活性.
- 开发出有效的NSD2降解剂,诱导蛋白质降解,降低H3K36me2水平,并抑制癌细胞增殖.
结论:
- 针对NSD2 PWWP1域的小分子配体提供了一个新的治疗策略.
- 针对性降低NSD2是一种可行的方法来治疗NSD2驱动的癌症.
- 通过降解抑制NSD2活动,降低瘤原体组胺甲基化,抑制瘤细胞生长.
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