BET in hematologic tumors: Immunity, pathogenesis, clinical trials and drug combinations

Ma, Tao; Chen, Yan; Yi, Zhigang; Li, Yanhong; Bai, Jun; Li, Lijuan; Zhang, Liansheng

doi:10.1016/j.gendis.2022.03.004

Cited by 7 publications

(3 citation statements)

References 128 publications

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

confidence: 99%

“…The bromodomain and extra-terminal domain (BET) protein family plays a vital role in epigenetic and transcriptional regulation [ 104 , 105 , 106 ]. Its immuno-regulating function is mainly associated with PD-L1 expression, which is mediated by bromodomain-containing protein 4 (BRD4) [ 104 , 105 , 107 ]. Small-molecule BET inhibitors (BETi) are demonstrated to noticeably reduce PD-L1 in mRNA and protein levels in several cancers, such as melanoma, triple-negative breast cancer (TNBC), liver cancer, and lung cancer [ 108 , 109 ].…”

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

confidence: 99%

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

confidence: 99%

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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“…Among the various members of the BET family, there is a BRD4, which is a nuclear protein involved in the organization and regulation of genetic transcription of relevant genes (e.g., c‐Myc, BCL‐XL, BCL‐2) 118,119 . Although its role is not yet completely clear in cancer development, since recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation, it is known that the BRD4 protein is often found overexpressed and abnormally activated in several types of cancer, including AML, ALL, and CML, and has therefore been extensively studied as a promising target involved in tumorigenesis and tumor progression 120,121 …”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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