2. Academic Validation
  3. Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment

  • J Med Chem. 2024 Jun 24. doi: 10.1021/acs.jmedchem.4c00296.
Yuan Gao 1 2 3,  Ji-Long Duan 1 2,  Chen-Chen Wang 4,  Yinghui Yuan 1 2,  Pengpeng Zhang 1 2,  Zong-Hao Wang 1 2,  Bowen Sun 1 2,  Jiawei Zhou 1 2,  Xiaoli Du 1 2,  Xiawen Dang 1 2,  Rui-Ting Bai 1 2,  Hang Zhang 1 2 4,  Tian Xie 1 2,  Xiang-Yang Ye 1 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Hangzhou Normal University, Zhejiang, Hangzhou 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, Zhejiang Hangzhou 311121, China.
  • 3 Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, China.
  • 4 College of Life and Environmental Sciences, Hangzhou Normal University, Zhejiang, Hangzhou 311121, China.
PMID: 38912753 DOI: 10.1021/acs.jmedchem.4c00296
Abstract

Bifunctional conjugates targeting PD-L1/PARP7 were designed, synthesized, and evaluated for the first time. Compounds B3 and C6 showed potent activity against PD-1/PD-L1 interaction (IC50 = 0.426 and 0.342 μM, respectively) and PARP7 (IC50 = 2.50 and 7.05 nM, respectively). They also displayed excellent binding affinity with hPD-L1, approximately 100-200-fold better than that of hPD-1. Both compounds restored T-cell function, leading to the increase of IFN-γ secretion. In the coculture assay, B3 and C6 enhanced the killing activity of MDA-MB-231 cells by Jurkat T cells in a concentration-dependent manner. Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential Anticancer therapy.

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