Discovery of 4-phenyl-1H-indazole derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction

Chenglong Xu; Zhiqiang Sun; Xuewen Zhang; Qinru Zang; Zichao Yang; Ling Li; Xixiang Yang; Yueyu He; Zeli Ma; Jianjun Chen

doi:10.1016/j.bioorg.2024.107376

Discovery of 4-phenyl-1H-indazole derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction

Bioorg Chem. 2024 Apr 16:147:107376. doi: 10.1016/j.bioorg.2024.107376. Online ahead of print.

Authors

Chenglong Xu¹, Zhiqiang Sun¹, Xuewen Zhang¹, Qinru Zang¹, Zichao Yang¹, Ling Li², Xixiang Yang¹, Yueyu He¹, Zeli Ma³, Jianjun Chen⁴

Affiliations

¹ Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
² The Eighth Affiliated Hospital, Sun Yat sen University, Shenzhen 518033, China.
³ Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
⁴ Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jchen21@smu.edu.cn.

PMID: 38640722
DOI: 10.1016/j.bioorg.2024.107376

Abstract

The inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway with small molecules is a promising approach for cancer immunotherapy. Herein, novel small molecules compounds bearing various scaffolds including thiophene, thiazole, tetrahydroquinoline, benzimidazole and indazole were designed, synthesized and evaluated for their inhibitory activity against the PD-1/PD-L1 interaction. Among them, compound Z13 exhibited the most potent activity with IC₅₀ of 189.6 nM in the homogeneous time-resolved fluorescence (HTRF) binding assay. Surface plasmon resonance (SPR) assay demonstrated that Z13 bound to PD-L1 with high affinity (K_D values of 231 nM and 311 nM for hPD-L1 and mPD-L1, respectively). In the HepG2/Jurkat T co-culture cell model, Z13 decreased the viability rate of HepG2 cells in a concentration-dependent manner. In addition, Z13 showed significant in vivo antitumor efficacy (TGI = 52.6 % at 40 mg/kg) without obvious toxicity in the B16-F10 melanoma model. Furthermore, flow cytometry analysis demonstrated that Z13 inhibited tumor growth in vivo by activating the tumor immune microenvironment. These findings indicate that Z13 is a promising PD-1/PD-L1 inhibitor deserving further investigation.

Keywords: 4-phenyl-1H-indazole; Immunotherapy; PD-1/PD-L1.