Fiorentino Francesco, Spriano Filippo, Tomaselli Daniela, Risi Giorgia, Fabbrizi Emanuele, Pecci Valeria, Nanni Simona, Bertoni Francesco, Rotili Dante, Mai Antonello
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
Faculty of Biomedical Sciences, Institute of Oncology Research, USI Bellinzona, 6500, Bellinzona, Switzerland.
ChemMedChem. 2025 Apr 1:e2400792. doi: 10.1002/cmdc.202400792.
The alteration of the lysine acetyltransferase activity and protein-protein interactions of the transcriptional co-activators CREB-binding protein (CBP) and p300 is linked to the development of both solid and hematological cancers. To target both functions of CBP/p300, two PROTAC-based chemical degraders are developed by linking the CBP/p300 catalytic inhibitor C646 and the Cereblon (CRBN) ligand thalidomide via polyethylene glycol-based linkers. Both compounds exhibit submicromolar inhibition of CBP/p300 and decrease their levels in the SU-DHL-10 lymphoma cell line at low-micromolar concentrations. Moreover, it is demonstrated that compound 1 recruits CBP/p300 and CRBN in cells and acts as a bona fide PROTAC degrader of CBP/p300 via the ubiquitin-proteasome pathway. Finally, both compounds exhibit low-micromolar antiproliferative activity in different lymphoma cell lines and are more potent than C646. Overall, it is demonstrated that the PROTAC strategy is a viable option for targeting CBP/p300 in lymphoma and identifies compound 1 as a promising chemical tool and lead compound for further studies.
赖氨酸乙酰转移酶活性的改变以及转录共激活因子 CREB 结合蛋白（CBP）和 p300 的蛋白质 - 蛋白质相互作用与实体癌和血液系统癌症的发生发展均有关联。为了针对 CBP/p300 的这两种功能，通过基于聚乙二醇的连接子将 CBP/p300 催化抑制剂 C646 和 Cereblon（CRBN）配体沙利度胺连接起来，开发了两种基于 PROTAC 的化学降解剂。这两种化合物对 CBP/p300 均表现出亚微摩尔级别的抑制作用，并在低微摩尔浓度下降低了它们在 SU-DHL-10 淋巴瘤细胞系中的水平。此外，还证明了化合物 1 在细胞中招募 CBP/p300 和 CRBN，并通过泛素 - 蛋白酶体途径作为 CBP/p300 的真正 PROTAC 降解剂发挥作用。最后，这两种化合物在不同的淋巴瘤细胞系中均表现出低微摩尔级别的抗增殖活性，且比 C646 更有效。总体而言，证明了 PROTAC 策略是针对淋巴瘤中 CBP/p300 的可行选择，并将化合物 1 鉴定为有前景的化学工具和用于进一步研究的先导化合物。
