Representative achievement 1: Original drug development
We have conducted concentrated and in-depth research on the discovery and development of regulators targeting inflammation and immune-related targets, such as Nrf2 transcription factor, NLRP3 inflammasome, and P2Y14R receptor, including: (1) discovery, structure modification, target identification, and structure-activity relationship studies of novel 1,2,4-oxadiazole Nrf2 activators; (2) development of novel tetrahydroquinoline NLRP3 inflammasome-targeting inhibitors and their therapeutic effects in a DSS-induced colitis model; (3) study of a series of anti-inflammatory P2Y14R antagonists, 5-amino-1H-pyrazole-3-carboxylic acid derivatives. Some breakthrough achievements have been made, such as: J. Med. Chem. 2015, 58, 5419−5436.; J. Med. Chem., 2021, 64, 871–889.; J. Med. Chem., 2022, 65, 23, 15967–15990.
Representative achievement 2: Drug target discovery and validation
Previous studies by our team have shown that 1,2,4-oxadiazole Nrf2-ARE activators obtained through phenotype screening are non-selective inhibitors of NLRP3 inflammasome and have broad therapeutic effects on various inflammation-related diseases. However, the specific target protein of these molecules is still unknown, which hinders further drug development. Combining small molecule probes and proteomics techniques, it was found that DDO-7263 activates the Nrf2-ARE antioxidant pathway by blocking the assembly of the 26S proteasome and ubiquitination of Nrf2 through binding to the Rpn6 protein. The research results have been published in authoritative journals such as J. Med. Chem. 2022, 65, 5029−5043.; Free Radic. Biol. Med. 2019, 134, 288–303. Eur. J. Med. Chem. 2018, 157, 1376-1394.; J. Med. Chem. 2015, 58, 5419−5436.
Representative achievement 3: New analytical method and development
A new method for detecting IDO1 enzyme activity was developed based on supramolecular fluorescence probes. The reliability of the method was validated at both the in vitro and cellular levels, and was compared to traditional HPLC and absorbance methods. This method was creatively used to detect IDO1 enzyme activity at the cellular level, and two compounds with inhibitory activity were screened from an unknown compound library using this method. This provides a new approach for developing new IDO1 inhibitors in the future. The research results have been published in authoritative journals of drug analysis Anal. Chem. 2019, 91 (23), 14943-14950.
1.Original drug research and development
2.Discovery and confirmation of drug target
3.Development of new analytical methods related to drug control
Representative achievement 1: Original drug development
We have conducted concentrated and in-depth research on the discovery and development of regulators targeting inflammation and immune-related targets, such as Nrf2 transcription factor, NLRP3 inflammasome, and P2Y14R receptor, including: (1) discovery, structure modification, target identification, and structure-activity relationship studies of novel 1,2,4-oxadiazole Nrf2 activators; (2) development of novel tetrahydroquinoline NLRP3 inflammasome-targeting inhibitors and their therapeutic effects in a DSS-induced colitis model; (3) study of a series of anti-inflammatory P2Y14R antagonists, 5-amino-1H-pyrazole-3-carboxylic acid derivatives. Some breakthrough achievements have been made, such as: J. Med. Chem. 2015, 58, 5419−5436.; J. Med. Chem., 2021, 64, 871–889.; J. Med. Chem., 2022, 65, 23, 15967–15990.
Representative achievement 2: Drug target discovery and validation
Previous studies by our team have shown that 1,2,4-oxadiazole Nrf2-ARE activators obtained through phenotype screening are non-selective inhibitors of NLRP3 inflammasome and have broad therapeutic effects on various inflammation-related diseases. However, the specific target protein of these molecules is still unknown, which hinders further drug development. Combining small molecule probes and proteomics techniques, it was found that DDO-7263 activates the Nrf2-ARE antioxidant pathway by blocking the assembly of the 26S proteasome and ubiquitination of Nrf2 through binding to the Rpn6 protein. The research results have been published in authoritative journals such as J. Med. Chem. 2022, 65, 5029−5043.; Free Radic. Biol. Med. 2019, 134, 288–303. Eur. J. Med. Chem. 2018, 157, 1376-1394.; J. Med. Chem. 2015, 58, 5419−5436.
Representative achievement 3: New analytical method and development
A new method for detecting IDO1 enzyme activity was developed based on supramolecular fluorescence probes. The reliability of the method was validated at both the in vitro and cellular levels, and was compared to traditional HPLC and absorbance methods. This method was creatively used to detect IDO1 enzyme activity at the cellular level, and two compounds with inhibitory activity were screened from an unknown compound library using this method. This provides a new approach for developing new IDO1 inhibitors in the future. The research results have been published in authoritative journals of drug analysis Anal. Chem. 2019, 91 (23), 14943-14950.
[1] Dai, Z.#; An, L. Y.#; Chen, X. Y. #; et al; You, Q. D.*; Di, B.*; Xu, L. L.* Target fishing reveals a novel mechanism of 1,2,4-oxadiazole derivatives targeting to Rpn6, a subunit of 26S Proteasome, Journal of Medicinal Chemistry, 2022, 65, 5029−5043. (SCI, IF = 8.039)
[2] Wang Y. H.#; Zhou M. Z.#; Ye Ta; Wang P. P.; Lu R.; Wang Y. L.; Liu C. X.; Xiao W.; Li J. Y.; Meng Z. B.; Xu L. L. *; Hu Q. H. *; and Jiang C.* Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y14R Antagonists with Anti-Inflammatory Characters. Journal of Medicinal Chemistry, 2022, 65, 23, 15967–15990. (SCI, IF = 8.039)
[3] Dai, Z.; Chen, X. Y.; An, L. Y.; Li, C. C.; Zhao, N.; Yang, F.; You, S. T.; Hou, C. Z.; Li, K.; Jiang, C.*; You, Q. D.*; Di, B.*; Xu, L. L.*, Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse, Journal of Medicinal Chemistry, 2021, 64, 871-889. (SCI, IF = 8.039)
[4] Li, C. C.; Zhao, N.; An, L. Y.; Dai, Z.; Chen, X. Y.; Yang, F.; You, Q. D.; Di, B.*; Hu, C.*; Xu, L. L.*, Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASG12C, Acta Pharmaceutica Sinica B, 2021, 11(9), 2670e2684. (SCI, IF = 14.907)
[5] Zhao, N.; Di, B.*; Xu, L. L.*, The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies. Cytokine and Growth Factor Reviews, 2021, 61, 2–15. (SCI, IF = 17.660)
[6] Zhao, N.; Li, C. C.; Di, B.*; Xu, L. L.*, Recent advances in the NEK7-licensed NLRP3 inflammasome activation: Mechanisms, role in diseases and related inhibitors, Journal of Autoimmunity, 2020, 113, 102515. (SCI, IF = 14.511)
[7] Cheng, S.; Shen, H.; Zhao, S.; Zhang, Y.; Xu, H.; Wang, L.; Di, B.*; Xu, L. L.*; Hu, C.*, Orally administered mesoporous silica capped with the cucurbit[8]uril complex to combat colitis and improve intestinal homeostasis by targeting the gut microbiota, Nanoscale, 2020, 12(28), 15348-15363. (SCI, IF = 8.307)
[8] Xu, L. L.; Li, C. C.; An, L. Y.; Dai, Z.; Chen, X. Y.; You, Q. D.*; Hu, C.*; Di, B.*, Selective apoptosis-inducing activity of synthetic hydrocarbon-stapled SOS1 helix with D-amino acids in H358 cancer cells expressing KRASG12C, European Journal of Medicinal Chemistry, 2020, 185, 111844. (SCI, IF = 7.088)
[9] Jia, J.; Wen, H.; Zhao, S.; Wang, L.; Qiao, H.; Shen, H.; Yu, Z.; Di, B.*; Xu, L. L.*; Hu, C.*, Displacement Induced Off-On Fluorescent Biosensor Targeting IDO1 Activity in Live Cells, Analytical Chemistry, 2019, 91 (23), 14943-14950. (SCI, IF = 8.008)
[10] Xu, L. L.; Wu, Y. F.; Yan, F.; Li, C. C.; Dai, Z.; You, Q. D*; Jiang, Z. Y.*; Di, B.*, 5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress, Free Radical Biology and Medicine, 2019,134, 288-303. (SCI, IF = 8.101)
