2. Academic Validation
  3. Discovery of (S)-N1-(thiazol-2-yl) pyrrolidine-1,2-dicarboxamide derivatives targeting PI3Ka/HDAC6 for the treatment of cancer

Discovery of (S)-N1-(thiazol-2-yl) pyrrolidine-1,2-dicarboxamide derivatives targeting PI3Ka/HDAC6 for the treatment of cancer

  • Bioorg Med Chem Lett. 2023 Oct 1:94:129462. doi: 10.1016/j.bmcl.2023.129462.
Yanfei Zhang 1,  Jinlai Gao 2,  Jiming Wu 2,  Shihui Liu 2,  Xiaoping Zhang 3,  Xiaoqing Lv 4
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; College of Medicine, Jiaxing University, Jiaxing 314001, China.
  • 2 College of Medicine, Jiaxing University, Jiaxing 314001, China.
  • 3 Department of Science and Education, the First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing 314001, China. Electronic address: zxp867@163.com.
  • 4 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; College of Medicine, Jiaxing University, Jiaxing 314001, China. Electronic address: lxqd1@126.com.
PMID: 37652098 DOI: 10.1016/j.bmcl.2023.129462
Abstract

Recently, PI3K and HDAC have been considered as promising targets for the Cancer therapy. A couple of pan-PI3K/HDAC dual inhibitors have been developed as a new class of Anticancer agents. Herein, we discovered a new series of (S)-N1-(thiazol-2-yl) pyrrolidine-1,2-dicarboxamide derivatives targeting PI3Kα/HDAC6. All the derivatives exerted dual-target inhibitory activities. Particularly, in the enzymatic selectivity assay, compound 21j was identified as a subtype-selective PI3Kα/HDAC6 dual inhibitor (IC50 = 2.9 and 26 nM against PI3Kα and HDAC6, respectively), which displayed high potency against L-363 cell line with IC50 value of 0.17 μM. In addition, 21j significantly inhibited phosphorylation of pAkt(Ser473) and induced accumulation of acetylated α-tubulin while having a negligible effect on the levels of acetylated Histone H3 and H4 at nanomolar level. Attributed to its favorable in vitro performance, 21j has the potential to alleviate the adverse effects resulted from pan-PI3K inhibition and pan-HDAC inhibition. It is valuable for further functional investigation as an anti-cancer agent.

Keywords

Anti-cancer; HDAC6; Inhibitor; PI3Kα.

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