2. Academic Validation
  3. Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition

Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition

  • J Med Chem. 2024 Mar 28;67(6):4950-4976. doi: 10.1021/acs.jmedchem.4c00090.
Ji-Long Duan 1 2,  Chen-Chen Wang 3,  Yinghui Yuan 1 2,  Zi Hui 1 2,  Hang Zhang 4,  Nian-Dong Mao 3,  Pengpeng Zhang 1 2,  Bowen Sun 1 2,  Jing Lin 5,  Zishuo Zhang 4,  Yuan Gao 1 6,  Tian Xie 1 2,  Xiang-Yang Ye 1 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 2 Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 3 College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 4 School of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 5 Drug Discovery, Hangzhou Haolu Pharma Ltd. Co., Hangzhou, Zhejiang 311121, China.
  • 6 Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, China.
PMID: 38456618 DOI: 10.1021/acs.jmedchem.4c00090
Abstract

Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 Inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between Anticancer immunity and HDAC inhibition.

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