作者: Hu, Jiankang ; Dong, Ruibo ; Xu, Hongrui ; Xu, Yong ; Zhao, Xiaofan ; Wu, Tianbang ; Xiang, Qiuping ; Zhang, Xiaohan ; Zhang, Yan ; Zhang, Cheng ; Shen, Hui ; Wu, Xishan ; Lin, Bin ; Hu, Qingqing

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 5. Among the compounds synthesized, 11c (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 5. Furthermore, 11c demonstrated significant inhibition of tumor growth in a MOLM-16 xenograft model (TGI = 60%) at tolerated dose schedules. Our findings suggest that 11c is a promising lead compound for the treatment of AML.

Nature Communications1区 · 综合性期刊

Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis

1区 · 综合性期刊

ArticleOA

作者: Lee, Eun Young ; Kim, Seong Soon ; Pagire, Suvarna H ; Goughnour, Peter C ; Oh, Chang Joo ; Pagire, Haushabhau S ; Kim, Dooseop ; Jeong, Byung-Kwan ; Lee, Hee Jong ; Ahn, Jin Hee ; Lim, Chae Won ; Lee, In-Kyu ; Song, Sungmin ; Loomba, Rohit ; Yoon, Jihyeon ; Bae, Myung Ae ; Jeon, Jae-Han ; Kim, Minhee ; Choi, Won-Il ; Kim, Hail

AbstractMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Based on recent findings by our team that liver 5HT2A knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT2A antagonist, compound 11c for MASH. It shows good in vitro activity, stability, and in vivo pharmacokinetics (PK) in rats and dogs. Compound 11c also shows good in vivo efficacy in a diet-induced obesity (DIO) male mice model and in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) male mice model, effectively improving histologic features of MASH and fibrosis. According to the tissue distribution study using [14C]-labeled 11c, the compound was determined to be a peripheral 5HT2A antagonist. Collectively, first-in-class compound 11c shows promise as a therapeutic agent for the treatment of MASLD and MASH.

Journal of Experimental & Clinical Cancer Research

The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance

Article

作者: Pantaleo, Antonino ; Lantone, Valerio ; Sanese, Paola ; Tubertini, Matilde ; Disciglio, Vittoria ; De Marco, Katia ; Naldi, Marina ; Spilotro, Vito ; La Rocca, Francesca ; Ferroni, Claudia ; Labarile, Nicoletta ; Del Rio, Alberto ; Armentano, Raffaele ; Lantone, Giuliano ; Simone, Cristiano ; Di Nicola, Elisabetta ; Varchi, Greta ; Bartolini, Manuela ; Fasano, Candida ; Forte, Giovanna ; Lepore Signorile, Martina ; Latrofa, Marialaura ; De Marinis, Lucia ; Bianco, Giusy ; Grossi, Valentina ; Gigante, Gianluigi

AbstractBackgroundSMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair.MethodsIn cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients’ residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs).ResultsHere we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models.ConclusionsOverall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.

100 项与 EM-127 相关的药物交易

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