Discovery of 4-Arylindolines Containing a Thiazole Moiety as Potential Antitumor Agents Inhibiting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

  • J Med Chem. 2021 May 13;64(9):5519-5534. doi: 10.1021/acs.jmedchem.0c01958.
Mingze Qin  1 ,  Yangyang Meng  1 ,  Haoshen Yang  2 ,  Lei Liu  1 ,  Haotian Zhang  2 ,  Simeng Wang  2 ,  Chunyang Liu  1 ,  Xia Wu  1 ,  Di Wu  1 ,  Ye Tian  1 ,  Yunlei Hou  1 ,  Yanfang Zhao  1 ,  Yajing Liu  1 ,  Congjun Xu  3 ,  Lihui Wang  2
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
PMID: 33938739 DOI: 10.1021/acs.jmedchem.0c01958
Abstract

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.