Insights into non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction: Development and perspective

Wu, Xia; Meng, Yangyang; Liu, Lei; Gong, Guowei; Zhang, Haotian; Hou, Yunlei; Liu, Chunyang; Wu, Di; Qin, Mingze

doi:10.1016/j.bmc.2021.116038

Cited by 12 publications

(11 citation statements)

References 63 publications

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“…S1B). Both of these interactions between BMS-202 and PD-L1 have been described in previous studies [ 44 , 45 ]. In addition, the oxygen atom of the amide group of BMS-202 formed a hydrogen bond with LsyA124 acting as an H-acceptor, and the protonated amine formed a metal contact with AspA122 (Additional file 1 : Fig.…”

Section: Resultssupporting

confidence: 63%

Identification of potential immunomodulators from Pulsatilla decoction that act on therapeutic targets for ulcerative colitis based on pharmacological activity, absorbed ingredients, and in-silico molecular docking

et al. 2022

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Background Pulsatilla decoction (Bai-Tou-Weng-Tang, BTWT) is a classic formula prescription of a traditional Chinese medicine that is used to treat ulcerative colitis (UC). However, its active components and underlying mechanism of action remain unclear. In the present study, we aimed to identify potential immunomodulators from BTWT that act at therapeutic targets for UC. Methods The protective effects of BTWT granules were examined in mice with colitis induced by dextran sulfate sodium. The absorbed components of BTWT were identified using LC-MS, and selected protein targets of these components in UC were investigated using molecular docking. Results Oral administration of BTWT granules significantly alleviated disease severity and colon shortening, and inhibited the inflammatory response in mice with chronic colitis. In these mice, 11 compounds from the BTWT granules were detected in the serum and/or colon. The molecular docking study demonstrated that compounds from Radix pulsatillae, such as anemoside A3, interacted with STAT3 and S1PR1; compounds from Rhizoma coptidis and/or Cortex phellodendri, such as palmatine, interacted with JAK3, PD-1, and PD-L1; and components of Cortex fraxini such as aesculin interacted with S1PR1, JAK3, STAT3 and PD-L1. Further in-vitro experiments showing that the compounds inhibited TNF-α and IL-6 production and STAT3 activation in RAW 264.7 cells suggested that these compounds have immunomodulatory activities. Conclusion We revealed for the first time that 11 absorbed ingredients from BTWT were immunomodulators against therapeutic targets for UC. These findings suggest that the identified compounds are the active components of BTWT, and the identified protein targets underlie the mechanism of action of BTWT against UC.

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Section: Resultssupporting

confidence: 63%

Identification of potential immunomodulators from Pulsatilla decoction that act on therapeutic targets for ulcerative colitis based on pharmacological activity, absorbed ingredients, and in-silico molecular docking

et al. 2022

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“…Cancer cells express PD-L1 on their surface to evade cytotoxic T lymphocytes (CTLs)-mediated tumor killing [ 84 , 85 , 86 ]. Cumulative evidence has shown the superiority of targeted degradation on long-term PD-L1 dysfunction over conventional antibody-based blockade [ 34 , 87 , 88 , 89 , 90 ].…”

Section: Small-molecule Protacs Targeting Pd-1/pd-l1 Checkpoint Signa...mentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

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“…However, oral immune PD-(L)1 programs are still in their infancy. In comparison with monoclonal antibodies, small-molecule PD-(L)1 inhibitors could overcome several shortcomings of monoclonal antibodies, such as low tumor penetration and high manufacturing costs ( 87 ). More importantly, small-molecule PD-(L)1 inhibitors possess the ability to manage immune-related AE due to their shorter pharmacokinetic exposure ( 88 , 89 ).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of VEGF and/or TGF-β to enhance anti-PD-(L)1 therapy: The evidence from clinical trials

Wen

Ding

2022

Front. Oncol.

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Normalizing the tumor microenvironment (TME) is a potential strategy to improve the effectiveness of immunotherapy. Vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways play an important role in the development and function of the TME, contributing to the immunosuppressive status of TME. To inhibit VEGF and/or TGF-β pathways can restore TME from immunosuppressive to immune-supportive status and enhance sensitivity to immunotherapy such as programmed death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. In this review, we described the existing preclinical and clinical evidence supporting the use of anti-VEGF and/or anti-TGF-β therapies to enhance cancer immunotherapy. Encouragingly, adopting anti-VEGF and/or anti-TGF-β therapies as a combination treatment with anti-PD-(L)1 therapy have been demonstrated as effective and tolerable in several solid tumors in clinical trials. Although several questions need to be solved, the clinical value of this combination strategy is worthy to be studied further.

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Insights into non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction: Development and perspective

Cited by 12 publications

References 63 publications

Identification of potential immunomodulators from Pulsatilla decoction that act on therapeutic targets for ulcerative colitis based on pharmacological activity, absorbed ingredients, and in-silico molecular docking

Identification of potential immunomodulators from Pulsatilla decoction that act on therapeutic targets for ulcerative colitis based on pharmacological activity, absorbed ingredients, and in-silico molecular docking

Small-Molecule PROTACs for Cancer Immunotherapy

Therapeutic targeting of VEGF and/or TGF-β to enhance anti-PD-(L)1 therapy: The evidence from clinical trials

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