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

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

NeoplasmsLeukemia

Inactive Indication-

Originator Organization

Dana-Farber Cancer Institute, Inc.

Active Organization

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

Harvard Medical School

Dana-Farber Cancer Institute, Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC38H37ClN8O7S

InChIKeyLKEGXJXRNBALBV-PMCHYTPCSA-N

CAS Registry1799711-21-9

100 Clinical Results associated with dBET1(Dana-Farber Cancer Institute)

100 Translational Medicine associated with dBET1(Dana-Farber Cancer Institute)

100 Patents (Medical) associated with dBET1(Dana-Farber Cancer Institute)

Literatures (Medical) associated with dBET1(Dana-Farber Cancer Institute)

13 Feb 2025·Journal of Medicinal Chemistry

Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs

Article

Author: Roussel, Martine F. ; Yang, Lei ; Marsh, Graham ; Hughes, Gareth ; Murphy, Nancy ; Li, Yong ; Steger, Martin ; Cresser-Brown, Joel ; Wheeler, Dean ; Daub, Henrik ; Aggarwal, Anup ; Riching, Kristin M. ; Caine, Elizabeth A. ; Mayasundari, Anand ; Schwalb, Björn ; Nishiguchi, Gisele ; Fu, Xiang ; Karadogan, Burhan ; Actis, Marisa ; Norley, Mark ; Urh, Marjeta ; Spain, Freya ; Rankovic, Zoran ; Valinciute, Gintvile ; Maple, Hannah

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall in vitro degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor in vivo pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (8), and results of a comprehensive in vitro/vivo comparative study with analogues containing alternative CRBN-directing warheads. Our study highlights the importance of considering warhead modifications when optimizing PROTACs for oral delivery.

09 Jan 2025·Journal of Medicinal Chemistry

Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions

Article

Author: Vellore, Nadeem A. ; Shi, Zhicai ; Audu, Christopher O. ; Zhang, Zirong ; Cernak, Tim ; Zhu, Lu ; Gelin, Christine F. ; Huang, Haiyan ; Brazeau, Jean-Francois ; Venable, Jennifer D. ; McGrath, Andrew

Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds. While straightforward to synthesize, amides may impart suboptimal drug properties to the overall molecule. From a systems level perspective, we envisioned that the potency of PROTACs could be modulated through selection of reaction conditions─wherein different catalysts produce distinct linkers from the same two building blocks. We present a suite of BRD4 PROTAC degraders prepared via four new amine-acid coupling reactions alongside the classic amide coupling. Our findings reveal that variations in reaction conditions affect the physicochemical properties of PROTACs, resulting in a spectrum of properties. Notably, several new PROTACs demonstrated enhanced BRD4 degradation efficacy compared to those employing amide linkers, emphasizing the potential of systems chemistry as a therapeutic optimization strategy.

09 Oct 2024·Journal of the American Chemical Society

ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy

Article

Author: Zhang, Xiangdong ; Teng, Xucong ; Zhang, Qiushuang ; Li, Jinghong ; Hu, Difei ; Zhao, Xuan ; Dai, Yicong ; Wu, Yuncong

Proteolysis-targeting chimeras (PROTACs) show promise in tumor treatment. However, the E3 ligases VHL and CRBN, commonly used in PROTAC, are highly expressed in only a few tumors, thus limiting the application scope and efficacy of PROTAC drugs. Furthermore, the lack of tumor specificity in PROTAC drugs can result in toxic side effects. Therefore, there is an urgent need to develop tumor-selective PROTAC drugs that do not rely on endogenous E3 ligases. In this study, we introduce the ClickRNA-PROTAC system, which involves the expression of a fusion protein of the E3 ubiquitin ligase SIAH1 and SNAPTag through mRNA transfection and recruits the protein of interest (POI) using bio-orthogonal click chemistry. ClickRNA-PROTAC can effectively degrade various proteins such as BRD4, KRAS, and NFκB simply by replacing the warhead molecules. By employing a tumor-specific mRNA-responsive translation strategy, ClickRNA-PROTAC can selectively degrade POIs in tumor cells. Furthermore, ClickRNA-PROTAC demonstrated strong efficacy in targeted cancer therapy in a xenograft mouse model of adrenocortical carcinoma. In conclusion, this approach offers several advantages, including independence from endogenous E3 ubiquitin ligases, tumor specificity, and programmability, thereby paving the way for the development of PROTAC drugs.

100 Deals associated with dBET1(Dana-Farber Cancer Institute)

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	Harvard Medical School	11 Jun 2018
Leukemia	Preclinical	United States	Dana-Farber Cancer Institute, Inc.	19 Jun 2015

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dBET1(Dana-Farber Cancer Institute)

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