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      Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials


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          Protein–protein interactions (PPIs) have pivotal roles in life processes. The studies showed that aberrant PPIs are associated with various diseases, including cancer, infectious diseases, and neurodegenerative diseases. Therefore, targeting PPIs is a direction in treating diseases and an essential strategy for the development of new drugs. In the past few decades, the modulation of PPIs has been recognized as one of the most challenging drug discovery tasks. In recent years, some PPIs modulators have entered clinical studies, some of which been approved for marketing, indicating that the modulators targeting PPIs have broad prospects. Here, we summarize the recent advances in PPIs modulators, including small molecules, peptides, and antibodies, hoping to provide some guidance to the design of novel drugs targeting PPIs in the future.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Live or let die: the cell's response to p53.

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              Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

              Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.

                Author and article information

                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                23 September 2020
                23 September 2020
                : 5
                : 213
                [1 ]GRID grid.54549.39, ISNI 0000 0004 0369 4060, Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, School of Medicine, , University of Electronic Science and Technology of China, ; 610072 Chengdu, China
                [2 ]GRID grid.410646.1, ISNI 0000 0004 1808 0950, Department of Ultrasonic, , Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, ; 610072 Chengdu, China
                [3 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Cancer Center, West China Hospital, , Sichuan University and Collaborative Innovation Center for Biotherapy, ; 610041 Sichuan, China
                [4 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Miller School of Medicine, , University of Miami, ; Miami, FL 33136 USA
                [5 ]GRID grid.411304.3, ISNI 0000 0001 0376 205X, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicines of Ministry, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Pharmacy College, , Chengdu University of Traditional Chinese Medicine, ; 611137 Chengdu, China
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                : 29 April 2020
                : 15 July 2020
                : 23 July 2020
                Funded by: FundRef https://doi.org/10.13039/501100010822, Chengdu Science and Technology Bureau;
                Award ID: No. 2015-HM01-00463-SF
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100005891, State Administration of Traditional Chinese Medicine of the People’ Republic of China (State Administration of Traditional Chinese Medicine);
                Award ID: JDZX2015210
                Award Recipient :
                Funded by: the Open Research Fund of Chengdu University of Traditional Chinese Medicine Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China (2018GZ2011005)
                Funded by: the Key Research and Development Program of Science and Technology Department of Sichuan Province(2019YFS0514)
                Review Article
                Custom metadata
                © The Author(s) 2020

                target identification,drug discovery
                target identification, drug discovery


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