Molecular mechanisms of cereblon-based drugs

Asatsuma‐Okumura, Tomoko; Ito, Takumi; Handa, Hiroshi

doi:10.1016/j.pharmthera.2019.06.004

Cited by 50 publications

(44 citation statements)

References 77 publications

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“…99 Similarly, immunomodulatory imide drugs (IMiDs), such as the teratogen thalidomide, are being repurposed on the strength of their ability to stabilize binding of E3 ligases to several lymphoid transcription factors. 100 A new strategy is also being explored to design bifunctional molecules, called PROTACs (proteolysis targeting chimera) or degraders, that recognize a common site on the surface of an E3 and a specific binding site on the surface of a target protein, bringing them together to promote targeted degradation. 101 Recently-…”

Section: E3 Ubiquitin Ligase Structures In the Pdbmentioning

confidence: 99%

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

et al. 2019

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Section: E3 Ubiquitin Ligase Structures In the Pdbmentioning

confidence: 99%

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

et al. 2019

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“…The primary target of thalidomide is cereblon which forms an E3 ligase complex with disrupted DNA-binding protein 1 and cullin-4A. The drug selectively binds with cereblon, thereby, inhibit its associated ubiquitin ligase activity [ 236 , 237 ]. Another mdm2 antagonist, MI-312 with cisplatin combined treatment, act synergistically, thereby suppressing cell growth and inducing apoptosis.…”

Section: Cancer Therapeutic Strategy Via Targeting Upsmentioning

confidence: 99%

Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling

Sharma

Khan

Singh

et al. 2021

IJMS

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The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.

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“…Proteolysis targeting chimeras (PROTACs) is composed of two molecules binding a target protein with an E3 ubiquitin ligase, promoting target intracellular ubiquitination. dBET1 is a PROTAC, composed of thalidomide and JQ1; the latter binds bromodomain and extra-terminal motif transcription factor (BET, specifically BRD4) promoting its degradation [ 57 ]. BRD4 is a chromatin reader protein that acts as a transcriptional coactivator involved in physiological hematopoiesis and is recruited in cancer development.…”

Section: New Moleculesmentioning

confidence: 99%

Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment

Piccolomo

Schifone

Strafella

et al. 2020

Cancers

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Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the tumor microenvironment. Recently IMiDs have been investigated for their pleiotropic properties and their therapeutic applications in both solid tumors (melanoma, prostate carcinoma and differentiated thyroid cancer) and hematological malignancies. Nowadays, they are applied in de novo and relapsed/refractory multiple myeloma, in myelodysplastic syndrome, in del5q syndrome with specific use of lenalidomide and B-cell lymphoma. Several studies have been conducted in the last few years to explore IMiDs possible use in acute myeloid leukemia treatment. Here we report the mechanisms of action of IMiDs in acute myeloid leukemia and their potential future therapeutic application in this disease.

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Molecular mechanisms of cereblon-based drugs

Cited by 50 publications

References 77 publications

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling

Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment

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