76350-90-8Relevant articles and documents
Molecular hybridization used to design and synthesize neo-tanshinlactone derivatives as PD-1/PD-L1 inhibitors
Lee, Kuo-Hsiung,Liu, Jianmin,Morris-Natschke, Susan,Wang, Ping,Wang, Yue,Zhang, Menghan
, (2022/01/13)
Four series of molecular hybrids (37 final products) of neo-tanshinlactone, a natural product extracted from Salvia miltiorrhiza Bunge, and known PD-1/PD-L1 interaction inhibitors were prepared as possible chemotherapeutic agents against triple negative breast cancer. Screening using a homogenous time-resolved fluorescence method resulted in three lead compounds (MZ52 IC50 74 ± 4 nM; MZ58 IC50 134 ± 17 nM; MZ61 IC50 225 ± 19 nM). With less T cell cytotoxicity and effects in activating CD8+ T cells in a T cell proliferation assay and a functionality experiment, MZ58 was selected as the best candidate for animal experiments. MZ58 exhibited antitumor effects in a subcutaneous transplantation tumor model as well as effects in reducing T cell exhaustion. In conclusion, after in vivo and in vitro experiments, we successfully acquired an effective candidate (MZ58) showing antitumor effects with low cytotoxicity toward T cells as well as the ability to activate CD8+ T cells and reduce T cell exhaustion.
In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)
Wang, Yubo,Zhou, Yuanyuan,Cao, Sheng,Sun, Yue,Dong, Zhiqiang,Li, Chen,Wang, Haoran,Yao, Yuhong,Yu, Haiyan,Song, Xiangyi,Li, Ming,Wang, Jiefu,Wei, Mingming,Yang, Guang,Yang, Cheng
supporting information, (2021/04/12)
Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.
Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
Butera, Roberto,Wa?yńska, Marta,Magiera-Mularz, Katarzyna,Plewka, Jacek,Musielak, Bogdan,Surmiak, Ewa,Sala, Dominik,Kitel, Radoslaw,De Bruyn, Marco,Nijman, Hans W.,Elsinga, Philip H.,Holak, Tad A.,D?mling, Alexander
supporting information, p. 768 - 773 (2021/05/31)
The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand their mode of action. In this work, we designed a new scaffold based on our previously solved high-resolution structures of low-molecular-weight inhibitors bound to PD-L1. A small compound library was synthesized using the Groebke-Blackburn-Bienaymé multicomponent reaction (GBB-3CR), resulting in the structure-activity relationship of imidazo[1,2-a]pyridine-based inhibitors. These inhibitors were tested for their biological activity using various biophysical assays giving potent candidates with low-micromolar PD-L1 affinities. An obtained PD-L1 cocrystal structure reveals the binding to PD-L1. Our results open the door to an interesting bioactive scaffold that could lead to a new class of PD-L1 antagonists.
