发现一种有前景的 CBP/p300 降解剂 XYD129 可用于治疗急性髓系白血病。
Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia.
机构信息
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
出版信息
J Med Chem. 2024 Jun 13;67(11):9194-9213. doi: 10.1021/acs.jmedchem.4c00335. Epub 2024 Jun 3.
The epigenetic target CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) and its homologue p300 were promising therapeutic targets for the treatment of acute myeloid leukemia (AML). Herein, we report the design, synthesis, and evaluation of a class of CBP/p300 PROTAC degraders based on our previously reported highly potent and selective CBP/p300 inhibitor . Among the compounds synthesized, (XYD129) demonstrated high potency and formed a ternary complex between CBP/p300 and CRBN (AlphaScreen). The compound effectively degraded CBP/p300 proteins and exhibited greater inhibition of growth in acute leukemia cell lines compared to its parent compound . Furthermore, demonstrated significant inhibition of tumor growth in a MOLM-16 xenograft model (TGI = 60%) at tolerated dose schedules. Our findings suggest that is a promising lead compound for the treatment of AML.
表观遗传靶点 CREB（环磷酸腺苷反应元件结合蛋白）结合蛋白（CBP）及其同源物 p300 是治疗急性髓细胞白血病（AML）的有前途的治疗靶点。在此，我们报告了基于我们之前报道的高活性和选择性 CBP/p300 抑制剂的一类 CBP/p300 PROTAC 降解剂的设计、合成和评价。在所合成的化合物中，化合物 XYD129 表现出高活性，并在 CBP/p300 和 CRBN（AlphaScreen）之间形成三元复合物。该化合物有效地降解了 CBP/p300 蛋白，并且与母体化合物相比，在急性白血病细胞系中表现出更强的生长抑制作用。此外，化合物在可耐受剂量方案的 MOLM-16 异种移植模型中显示出显著的肿瘤生长抑制作用（TGI = 60%）。我们的研究结果表明，化合物 XYD129 是治疗 AML 的有前途的先导化合物。
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