Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the ‘Undruggable’ MYC in Pancreatic Cancer

Minko, Tamara

doi:10.1016/j.tips.2020.08.008

Cited by 35 publications

(23 citation statements)

References 15 publications

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“…The current ndings con rmed that CRBN expression played an essential role in the sensitivity of T-ALL cells to ARV-825, given that shRNA-mediated knockdown or overexpression of CRBN reduced and increased their sensitivity to ARV-825, respectively. These results indicated that the enhanced antileukemic effect of ARV-825 was closely related to CRBN, consistent with results in other tumors [18,33]. c-Myc is transcriptionally regulated by super-enhancers in several hematological malignancies.…”

Section: Discussionsupporting

confidence: 89%

BRD4 PROTAC Degrader ARV-825 Inhibits T-Cell Acute Lymphoblastic Leukemia by Targeting 'Undruggable' Myc-pathway Genes

You

Yang

et al. 2020

Preprint

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BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Targeting bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents, and ARV-825, comprising a BET inhibitor conjugated with cereblon, was recently shown to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV825 in T-ALL.MethodsExpression levels of the BET protein BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP).ResultsBRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with the BET inhibitors JQ1 and dBET1. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in T cell lines and in pediatric T-ALL patients. ConclusionsBRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

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Section: Discussionsupporting

confidence: 89%

BRD4 PROTAC Degrader ARV-825 Inhibits T-Cell Acute Lymphoblastic Leukemia by Targeting 'Undruggable' Myc-pathway Genes

You

Yang

et al. 2020

Preprint

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“…ARV-825 consists of OTX015 and the E3 ubiquitin ligase cereblon (CRBN) used in PROTAC technology via a flexible chemical linker, which could efficiently degrade BRD4 (27). ARV-825 has been studied to treat pancreatic cancer (30,31), vemurafenib-resistant melanoma (32), cholangiocarcinoma (33), thyroid carcinoma (34), acute myeloid leukemia (35,36,38), and neuroblastoma therapy (37). These studies demonstrated that ARV-825 had a more effective inhibition on BRD4 protein.…”

Section: Discussionmentioning

confidence: 99%

“…ARV-825 consists of OTX015 and the E3 ubiquitin ligase cereblon (CRBN) using PROTAC technology, which degraded BRD4 more efficiently ( 27 ). ARV-825 has been studied to treat pancreatic cancer ( 30 , 31 ), vemurafenib-resistant melanoma ( 32 ), cholangiocarcinoma ( 33 ), thyroid carcinoma ( 34 ), and acute myeloid leukemia ( 35 , 36 ). ARV-825 could play a critical role in neuroblastoma therapy ( 37 ) and T-cell acute lymphoblastic leukemia ( 38 ).…”

Section: Introductionmentioning

confidence: 99%

ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

et al. 2021

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ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

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“…The discovery of thalidomide's mechanism of action as a cereblon (CRBN) ligand in 2010 suggested a second E3 ligase recruiting moiety for common use ( 64 ) (see Hijacking the UPS: molecular glues section for further elaboration). Indeed, thalidomide and its derivatives (the “phthalimides” or “IMiDs”) have since been used in PROTACs to induce the degradation of numerous target proteins ( 59 , 64 , 65 , 66 , 67 , 68 ). Interestingly, as compared with VHL, the promiscuous CRBN has been shown to be more accepting of neosubstrate degradation thus far ( 69 ).…”

Section: Hijacking Of the Ups: Protacsmentioning

confidence: 99%

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Alabi

Crews

2021

Journal of Biological Chemistry

155

122

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Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. By co-opting protein degradation pathways, TPD facilitates complete removal of the protein molecules from within or outside the cell. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway. Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. In this review, we discuss the major advances in TPD, highlight our current understanding, and explore outstanding questions in the field.

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Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the ‘Undruggable’ MYC in Pancreatic Cancer

Cited by 35 publications

References 15 publications

BRD4 PROTAC Degrader ARV-825 Inhibits T-Cell Acute Lymphoblastic Leukemia by Targeting 'Undruggable' Myc-pathway Genes

BRD4 PROTAC Degrader ARV-825 Inhibits T-Cell Acute Lymphoblastic Leukemia by Targeting 'Undruggable' Myc-pathway Genes

ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

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