76350-90-8Relevant academic research and scientific papers
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.
Proteolysis targeting chimera and application thereof
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Paragraph 0048-0050, (2021/07/14)
The invention provides a proteolysis targeting chimera and application thereof. According to a technical scheme in the invention, a novel PROTAC degradation agent compound 21a is developed on the basis of a BMS-37 small molecule. The novel PROTAC degradation agent compound 21a is an example of degrading membrane proteins on the basis of a ligand binding to the extracellular domain of a PD-L1 protein, and can effectively degrade PD-L1 in various malignant tumor cells. In-vivo research results show that after treatment with the compound 21a, the compound 21a can significantly reduce the level of the PD-L1 in tumors, promote infiltration of CD8T cells and significantly inhibit growth of mouse colorectal cancer MC-38 cells. The PROTAC molecule is expected to be one of novel and alternative strategies 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.
Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy in Vivo
Ouyang, Yiqiang,Gao, Jian,Zhao, Lei,Lu, Junfeng,Zhong, Haiqing,Tang, Hua,Jin, Shuanglong,Yue, Lu,Li, Yuezhen,Guo, Wenjie,Xu, Qiang,Lai, Yisheng
, p. 7646 - 7666 (2021/06/28)
Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1-31 and B1-17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.
Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects in Vivo
Guo, Jialin,Luo, Longlong,Wang, Zhihong,Hu, Naijing,Wang, Wei,Xie, Fei,Liang, Erguang,Yan, Xinlin,Xiao, Junhai,Li, Song
, p. 13825 - 13850 (2020/12/01)
A series of novel linear aliphatic amine-linked triaryl derivatives as inhibitors of PD-1/PD-L1 were designed, synthesized, and evaluated in vitro and in vivo. In this chemical series, compound 58 showed the most potent inhibitory activity and binding affinity with hPD-L1, with an IC50 value of 12 nM and a KD value of 16.2 pM, showing a binding potency approximately 2000-fold that of hPD-1. Compound 58 could bind with hPD-L1 on the cellular surface and competitively block the interaction of hPD-1 with hPD-L1. In a T cell function assay, 58 restored the T cell function, leading to increased IFN-γsecretion. Moreover, in a humanized mouse model, compound 58 significantly inhibited tumor growth without obvious toxicity and showed moderate PK properties after intravenous injection. These results indicated that 58 is a promising lead for further development of small-molecule PD-1/PD-L1 inhibitors for cancer therapy.
Pomalidomide derivative and application thereof
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Paragraph 0058-0060, (2020/07/13)
The invention relates to a pomalidomide derivative. The chemical structure of the pomalidomide derivative is shown as the following formula (I), in the formula (I), R1 is phenyl or 1, 4-benzodioxane,R2 is chlorine or bromine, R3 is hydrogen or a 3-methylbenzonitrile group, and X is a linking group selected from ethylenediamine, propane diamine, butanediamine, pentanediamine, hexamethylenediamine,piperazine succinic acid, piperazine glutaric acid, piperazine diglycolic acid, ethylenediamine succinic acid, ethylenediamine glutaric acid, ethylenediamine diglycolic acid, propane diamine glutaricacid, butanediamine glutaric acid or pentanediamine malonic acid. The pomalidomide derivative disclosed by the invention can inhibit the mutual combination of a programmed cell death receptor 1/a programmed cell death ligand 1 (PD-1/PD-L1), can be used for preparing a PD-1/PD-L1 inhibitor, and has a remarkable effect.
PYRIMIDINE DERIVATIVES AS INHIBITORS OF PD1/PD-L1 ACTIVATION
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Paragraph 000121, (2019/05/22)
The compounds of Formula Ib, Formula Ia, and Formula I are described herein along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof. The process of preparation of the compounds of Formula Ib, Formula Ia, and Formula I is also described. The compounds described herein, their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof are 2-(benzyloxy)pyrimidine derivatives that are inhibitors of PD-1/PD-L1 activation.
Fused ring compound and application thereof (by machine translation)
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Paragraph 0115; 0120-0121; 0128-0130, (2019/10/01)
The invention discloses a fused ring compound and application. The invention provides a compound, a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite, a stereoisomer, a tautomer or a prodrug. The compound I, provided by the invention, has the advantages of high activity, high bioavailability, stable medicine, oral administration, and the like. (by machine translation)
SUBSTITUTED 2,3-DIHYDRO-1H-INDENE ANALOGS AND METHODS USING SAME
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Page/Page column 44-45, (2018/11/22)
The present invention includes substituted 2,3-dihydro-1H-indene analogs, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) infections in a patient.
