BRD2 inhibitors(Bromodomain-containing protein 2 inhibitors), BRD3 inhibitors(Bromodomain-containing protein 3 inhibitors), BRD4 degraders(Bromodomain-containing protein 4 degraders)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication

Leukemia

Originator Organization

Harvard Medical School

Active Organization

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

Inactive Organization

Harvard Medical School

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC38H37ClN8O7S

InChIKeyLKEGXJXRNBALBV-PMCHYTPCSA-N

CAS Registry1799711-21-9

100 Clinical Results associated with dBET1(Harvard Medical School)

100 Translational Medicine associated with dBET1(Harvard Medical School)

100 Patents (Medical) associated with dBET1(Harvard Medical School)

Literatures (Medical) associated with dBET1(Harvard Medical School)

01 Sep 2024·International Immunopharmacology

A novel PROTAC molecule dBET1 alleviates pathogenesis of experimental autoimmune encephalomyelitis in mice by degrading BRD4

Article

Author: Li, Jin ; Tian, Jianan ; Wu, Yun ; He, Yijie ; Song, Ziwei ; Wang, Xiaokun

Neuroinflammation and neurodegeneration are hallmarks of multiple sclerosis (MS). Bromodomain-containing protein 4 (BRD4), a bromodomain and extra-terminal domain (BET) protein family member, is indispensable for the transcription of pro-inflammatory genes. Therefore, inhibiting BRD4 may be a prospective therapeutic approach for modulating the inflammatory response and regulating the course of MS. dBET1, a newly synthesized proteolysis-targeting chimera (PROTAC), exhibits effectively degrades of BRD4. However, the precise effects of dBET1 on MS require further investigation. Therefore, we assessed the effect of dBET1 in experimental autoimmune encephalomyelitis (EAE), a typical MS experimental model. Our findings revealed that BRD4 is mainly expressed in astrocytes and neurons of the spinal cords, and is up-regulated in the spinal cords of EAE mice. The dBET1 attenuated lipopolysaccharide-induced expression of astrocytic pro-inflammatory mediators and inhibited deleterious molecular activity in astrocytes. Correspondingly, dBET1, used in preventive and therapeutic settings, alleviated the behavioral symptoms in EAE mice, as demonstrated by decreased demyelination, alleviated leukocyte infiltration, reduced microglial and astrocyte activation, and diminished inflammatory mediator levels. In addition, dBET1 corrected the imbalance in peripheral T cells and protected blood-brain barrier integrity in EAE mice. The underlying mechanism involved suppressing the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase /extracellular signal-regulated kinase, and nuclear factor kappa B pathways. In summary, our data strongly suggests that dBET1 is a promising treatment option for MS.

01 Sep 2024·American Journal of Hematology

BRD4 degraders may effectively counteract therapeutic resistance of leukemic stem cells in AML and ALL

Article

Author: Hauswirth, Alexander ; Staber, Philipp B. ; Sperr, Wolfgang R. ; Koller, Elisabeth ; Thaler, Johannes ; Gleixner, Karoline V. ; Filik, Yüksel ; Valent, Peter ; Bettelheim, Peter ; Hoermann, Gregor ; Keil, Felix ; Bauer, Karin ; Greiner, Georg

AbstractAcute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are life‐threatening hematopoietic malignancies characterized by clonal expansion of leukemic blasts in the bone marrow and peripheral blood. The epigenetic reader BRD4 and its downstream effector MYC have recently been identified as potential drug targets in human AML and ALL. We compared anti‐leukemic efficacies of the small‐molecule BET inhibitor JQ1 and the recently developed BRD4 degraders dBET1 and dBET6 in AML and ALL cells. JQ1, dBET1, and dBET6 were found to suppress growth and viability in all AML and ALL cell lines examined as well as in primary patient‐derived AML and ALL cells, including CD34+/CD38− and CD34+/CD38+ leukemic stem and progenitor cells, independent of the type (variant) of leukemia or molecular driver expressed in leukemic cells. Moreover, we found that dBET6 overcomes osteoblast‐induced drug resistance in AML and ALL cells, regardless of the type of leukemia or the drug applied. Most promising cooperative or even synergistic drug combination effects were seen with dBET6 and the FLT3 ITD blocker gilteritinib in FLT3 ITD‐mutated AML cells, and with dBET6 and the multi‐kinase blocker ponatinib in BCR::ABL1+ ALL cells. Finally, all BRD4‐targeting drugs suppressed interferon‐gamma‐ and tumor necrosis factor‐alpha‐induced expression of the resistance‐related checkpoint antigen PD‐L1 in AML and ALL cells, including LSC. In all assays examined, the BRD4 degrader dBET6 was a superior anti‐leukemic drug compared with dBET1 and JQ1. Together, BRD4 degraders may provide enhanced inhibition of multiple mechanisms of therapy resistance in AML and ALL.

01 Nov 2023·Experimental and therapeutic medicine

BRD2 protects the rat H9C2 cardiomyocytes from hypoxia‑reoxygenation injury by targeting Nrf2/HO‑1 signaling pathway.

Article

Author: Xue, Xin ; Si, Liangyi ; Fu, Yuqing ; Liu, Yingcun ; Tang, Gang

Myocardial ischemia-reperfusion (I/R) injury is a common complication of acute myocardial infarction following percutaneous coronary intervention, but there are currently no effective pharmacological targets for adjuvant therapy due to a lack of knowledge of I/R injury mechanisms in cardiomyocytes. To evaluate the effects of hypoxia-reoxygenation on the plasma proteome of cardiomyocytes and prospective therapeutic targets, five sets of H9C2 cardiomyocytes from rats were cultured under various hypoxic circumstances. Using Cell Counting Kit-8 (CCK8) and lactose dehydrogenase (LDH) release assays, the cell viability and LDH release of H9C2 cells were analyzed. Proteome sequencing was then performed on cardiomyocytes to show the quantitative protein changes during the I/R injury process. After hypoxia/reoxygenation, bromodomain-containing protein 2 (BRD2) expression was evaluated. After administering the BRD2 inhibitor dBET1, the expression of nuclear factor erythroid 2-related factor 2/haem oxygenase-1 (Nrf2/HO-1) was identified. The results showed that in the group exposed to 4 h of hypoxia followed by 4 h of reoxygenation (H/R4), the cell survival rate was dramatically reduced, although the apoptotic rate and LDH were much higher than in the normal oxygen group. In addition, the expressions of 2,325 proteins differed considerably between these two groups, with 128 upregulated and 122 downregulated proteins being discovered in the H/R4 group. After 4 h of reoxygenation, the BRD2 expression was increased. Following the addition of dBET1 to suppress BRD2, the expression of Nrf2/HO-1 was reduced, but the rate of apoptosis increased. In conclusion, through the Nrf2/HO-1 signaling pathway, BRD2 protects cardiomyocytes from damage caused by hypoxia/reoxygenation. This may have implications for novel treatment targets to minimize I/R damage to the myocardium.

100 Deals associated with dBET1(Harvard Medical School)

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Leukemia	NDA/BLA	US	Harvard Medical School	08 Jun 2016
Neoplasms	Preclinical	CN	Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences	08 May 2019

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dBET1(Harvard Medical School)

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