Delving into the Latest Updates on dBET6(Dana-Farber Cancer Institute) with Synapse

Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms-

Target

BRD2 x BRD3 x BRD4

Action

inhibitors, degraders

Mechanism

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-

Originator Organization

Dana-Farber Cancer Institute, Inc.

Active Organization

Harvard Medical School

Dana-Farber Cancer Institute, Inc.

Inactive Organization

Novartis Institutes for Biomedical Research, Inc.

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC42H45ClN8O7S

InChIKeyJGQPZPLJOBHHBK-UFXYQILXSA-N

CAS Registry1950634-92-0

Author: Lingmin Zhang ; Wei, Juyan ; Liang, Lu ; Lei, Xueping ; Lu Liang ; Tang, Shiqi ; Li, Yuehua ; Liwu Fu ; Yu, Xi-Yong ; Xi-Yong Yu ; Yuehua Li ; Lin, Xufeng ; Linlong He ; Yinshan Lin ; Xufeng Lin ; Zhang, Lingmin ; Zhou, Dazhi ; Shiqi Tang ; Juyan Wei ; Juyun He ; Fu, Liwu ; He, Linlong ; Dazhi Zhou ; He, Juyun ; Lin, Yinshan ; Xueping Lei

Current pharmacotherapy on the fatal lung cancer is often limited by the development of drug resistance, which significantly contributes to treatment failure. The drug resistance in cancer is associated with tumor microenvironment (TME), particularly with cancer-associated fibroblasts (CAFs). However, the present approaches show little progress in the eliminating lung cancer cells and reversing the TME synergistically. The emergence of nanomedicine offers promising strategies to overcome this challenge. In this study, we developed a proteolysis-targeting chimeras (PROTAC)-based nanodrug, designed to eliminate both lung cancer cells and CAFs, thereby amplifying the therapeutic effects. This nanodrug was constructed by loading dBET6 with US Food and Drug Administration (FDA) approved polymer Poly(lactic-co-glycolic acid) (PLGA), and further camouflaged with the hybrid membranes derived from platelet and lung cancer cells (PLMPD). PLMPD demonstrated excellent dual-targeting capabilities to both lung cancer cells and CAFs, leading to significant apoptosis in both cell types in vitro. We also found that PLMPD could inhibited the growth of Osimertinib-resistant cells. In vivo studies revealed that PLMPD enhanced tumor targeting, effectively inhibited tumor growth, and reversed the tumor-promoting TME in the lung cancer xenograft models. These findings underscore the potential of PLMPD as a promising PROTAC-based nanodrug for lung cancer therapy, offering a new avenue for overcoming drug resistance and improving treatment outcomes.

01 Oct 2025·Clinical and Translational Medicine

Loss of Brd4 alleviates pathological bone loss via Slc9b2 suppression in osteoclastogenesis

Article

Author: Zha, Zhengang ; Zhang, Huan‐Tian ; Zheng, Xiaofei ; Zeng, Rong ; Xu, Chenhao ; Ju, Zhenyu ; Peng, Yuanshu ; Wong, Vincent Kam Wai ; Zheng, Boyuan ; Wang, Xiaohe ; Zhang, Xuguang ; Miao, Guiqiang ; Wang, Xiaogang ; Luo, Fangji ; Pang, Jinzhu

Abstract:

Background:

Epigenetic regulation plays a crucial role in skeletal degenerative diseases, including osteoporosis. As an epigenetic reader, bromodomain protein 4 (Brd4) is known as a key driver of gene activation; however, its role in maintaining skeletal homeostasis remains largely unknown.

Methods:

We examined Brd4 expression in bone specimens from osteoporotic patients and mouse models, and generated two types of Brd4 conditional knockout mice using Lyz2‐Cre and Ctsk‐Cre systems. Bone mass, osteoclast differentiation, and metabolic activity were assessed under physiological and pathological conditions, including ovariectomy and lipopolysaccharide (LPS) challenge. Mechanistic analyses were performed using transcriptomic screening, gene overexpression, and pharmacological interventions.

Results:

Brd4 expression was markedly elevated in bones from osteoporotic patients and mice compared with normal controls. Deletion of Brd4 increased basal bone mass and prevented bone loss induced by ovariectomy or LPS, primarily by suppressing osteoclastogenesis through inhibition of glycolysis. Unbiased screening identified solute carrier family 9 member B2 (Slc9b2) as a downstream effector of Brd4. Overexpression of Slc9b2 partially rescued the impaired osteoclastogenesis caused by Brd4 depletion. Moreover, phosphatidylserine‐containing nanoliposomes loaded with Brd4‐targeting PROTACs (e.g., dBET6) effectively suppressed osteoclastogenesis and alleviated pathological bone loss.

Conclusions:

Brd4 serves as a crucial regulator of osteoclast metabolism and differentiation. Targeting Brd4 represents a promising therapeutic strategy for the prevention and treatment of osteoporosis and pathological bone loss.

Key points:

Brd4 is highly expressed in osteoporotic patients and animals.Brd4 is crucial for glycolysis‐mediated OC differentiation.The loss of Brd4 in bone marrow monocytes or osteoclasts increases basal bone mass and prevents pathological bone loss.Slc9b2 is a novel target of Brd4 in mediating osteoclastogenesis.Targeting Brd4 by dBET6@PSLs could alleviate osteoporosis progression.

17 Jan 2025·ACS Chemical Biology

Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation

Article

Author: Müller, Susanne ; Menge, Amelie ; Knapp, Stefan ; Robers, Matthew B. ; Schwalm, Martin P. ; Elson, Lewis ; Greco, Francesco A.

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development and important tools for target validation. When appropriately optimized, both modalities lead to proteasomal degradation of the protein of interest (POI). Due to the complexity of the induced multistep degradation process, controls for degrader evaluation are critical and commonly used in the literature. However, comparative studies and evaluations of cellular potencies of these control compounds have not been published so far. Here, we investigated a diverse set of ubiquitin pathway inhibitors and evaluated their potency and utility within the CRBN and VHL-mediated degradation pathway. We used the HiBiT system to measure the level of target rescue after treatment with the control compounds. In addition, the cell health was assessed using a multiplexed high-content assay. These assays allowed us to determine nontoxic effective concentrations for control experiments and to perform rescue experiments in the absence of cellular toxicity.

100 Deals associated with dBET6(Dana-Farber Cancer Institute)

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