Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations

Tao

et al. 2020

Front. Oncol.

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Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting MYCN, a well-established driver gene in high-risk neuroblastoma, is still challenging. In recent years, inhibition of bromodomain and extra terminal (BET) proteins shows great potential in multiple of Myc-driven tumors. ARV-825 is a novel BET inhibitor using proteolysis-targeting chimera (PROTAC) technology which degrades target proteins by the proteasome. In this study, we investigated the effect of ARV-825 in neuroblastoma in vitro and in vivo. Our results showed that ARV-825 treatment robustly induced proliferative suppression, cell cycle arrest, and apoptosis in NB cells. Moreover, ARV-825 efficiently depleted BET protein expression, subsequently repressing the expression of MYCN or c-Myc. In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and MYCN expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve MYCN/c-Myc manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.

Section: Introductionmentioning

confidence: 75%

“…We previously reported that CRBN mRNA expression levels in different MM cell lines are correlated with their sensitivity to ARV-825 (29). In NB cells, three out of four NB cells have an appreciable expression of CRBN except for IMR-32 cells ( Figure 4A and Supplement Figure S4).…”

Section: Crbn Expression Is Indispensable To Sensitivity To Arv-825mentioning

confidence: 83%

PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc

Tao

et al. 2020

Front. Oncol.

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“…Therefore, new targeted therapies are urgently required. BET PROTAC and CDK9 inhibitors have shown promising results in preclinical studies against MM [4,5,19,20]. However, the limited clinical efficiency of CDK9 inhibitors due to side-effects and dose-limiting toxicities have prevented these drugs from receiving FDA approval.…”

Section: Discussionmentioning

confidence: 99%

“…This variety of inhibitor is called PROTAC (Proteolysis Targeting Chimeric molecules) which in this case causes ubiquitination of BET proteins resulting in rapid and efficient degradation of these proteins [3]. BET PRO-TAC ARV 825 inhibits the proliferation of MM cells both in vitro and in vivo [4,5].…”

Section: Introductionmentioning

confidence: 99%

Multiple myeloma: Combination therapy of BET proteolysis targeting chimeric molecule with CDK9 inhibitor

Han

et al. 2020

PLoS ONE

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Cyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 4573 and MC180295) against human multiple myeloma cells in vitro. Shorthairpin RNA silencing of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation. Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single agent alone. Combination treatment synergistically inhibited multiple myeloma cells both in vitro and in vivo with insignificant weight loss. The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells.

“…This variety of inhibitor is called PROTAC (Proteolysis Targeting Chimeric molecules) which in this case causes ubiquitination of BET proteins resulting in rapid and efficient degradation of these proteins 3 . BET PROTAC ARV 825 inhibits the proliferation of MM cells both in vitro and in vivo 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Multiple Myeloma: Combination Therapy of BET Proteolysis Targeting Chimeric Molecule with CDK9 Inhibitor

Koeffler

et al. 2020

Preprint

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22 Cyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain 23 (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II 24 C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 25 4573 and MC180295) against human multiple myeloma cells in vitro. Short-hairpin RNA silencing 26 of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells 27 showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 28 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter 29 drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation.30 Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein 31 expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single 32 agent alone. Combination treatment synergistically inhibited multiple myeloma cells both in vitro 33 and in vivo with insignificant weight loss. The combination also resulted in marked increase of 34 apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for 35 the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) 36 is effective against MM cells.37 38 39 40 41 3 42 Introduction: 43 Multiple myeloma (MM) is a clonal plasma cell malignancy. It is the second most common 44 hematologic malignancy in United States 1 . Despite advances in treatment such as proteasome 45 inhibitors and immunomodulatory drugs, the disease remains incurable. Bromodomain and Extra-46 Terminal Domain (BET) family is composed of BRD-2, -3, -4 and -T. They facilitates 47 4 64 and producing relapse in these patients 10,11 . Therefore, CDK9 may represent a druggable target in 65 myeloma having dysregulated MYC expression 12,13 . 66 67 Inhibition of both CDK9 and BRD 4 has been reported synergistically to induce growth arrest and 68 apoptosis of cancer cells including MM 14,15 . Previously studied CDK inhibitors (eg. Flavopiridol 69 and SNS-032) are not selective to CDK9, inhibiting other CDKs and enzymes. Their lack of 70selectivity and decreased potency may contribute to many adverse effects in clinical trials 8 . 71Therefore, selective inhibitors of CDK9 are needed to prevent the undesirable off-target effects 72 and to enhance potency. 73 74 AZD 4573 is highly potent against CDK9 (<3 nM IC 50 ) and selective (>10 fold) against CDK9. 75The drug results in caspase activation and loss of viability across a diverse set of hematological 76 cancers including MM 16 . MC180295 is also a highly selective CDK9 inhibitor (> 22 fold, IC 50 = 77 5 nM) that has broad anti-cancer activity in vitro and in vivo 17 . In this study, we noted that AZD 78 4573 and MC180295 in vitro inhibited the viability of MM cells. We also showed that AZD 4573 79 is synergistic with ARV 825 in inducing apoptosis and inhibiting MM cell proliferation both in 80 vitro and in v...