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Review
. 2024 Mar 19;17(3):392.
doi: 10.3390/ph17030392.

Identification and Development of BRD9 Chemical Probes

Ester Colarusso  1 , Maria Giovanna Chini  2 , Giuseppe Bifulco  1 , Gianluigi Lauro  1 , Assunta Giordano  3
Affiliations
Review

Identification and Development of BRD9 Chemical Probes

Ester Colarusso et al. Pharmaceuticals (Basel). .

Abstract

The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure-activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials.

Keywords: BRD9; PROTACs; drug discovery; inhibitors; leukemia; small molecules.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
(A) Human bromodomain phylogenetic tree. The Roman numerals (I to VIII) represent the different families. (B) Modular structure of most representative BET proteins and bromodomain-containing proteins of family IV.
Figure 2
Figure 2
BRD9 in the SWI/SNF remodeling complex orchestrates gene regulation by recognizing acetylated histones, contributing to chromatin accessibility, thus enabling transcription.
Figure 3
Figure 3
Structure of quinolone binders (compounds 3–6) and their hit compounds (compounds 1 and 2).
Figure 4
Figure 4
Structure of GSK2801 (compound 7) and GSK8573 (compound 8).
Figure 5
Figure 5
Structure of representative indolizine analogues (compounds 9–14).
Figure 6
Figure 6
Structure of [1,2,4]triazolo[4,3-a]phthalazine analogues (compounds 15–21).
Figure 7
Figure 7
Structure of bromosporine (compound 22) and bromotriazine (compound 23).
Figure 8
Figure 8
Structure of purine analogues (compounds 24–31).
Figure 9
Figure 9
Structure of alkyl-pyridazin-3(2H)-one analogues (compounds 32–39).
Figure 10
Figure 10
Structures of the first and the second series of triazoloquinoxaline analogues (compounds 40–49).
Figure 11
Figure 11
Structures of compounds 50–51.
Figure 12
Figure 12
Structures of thienopyridone analogues (compounds 52–58).
Figure 13
Figure 13
Structures of compounds 59–62.
Figure 14
Figure 14
Structures of the first series of pyridinone analogues (compounds 63–70).
Figure 15
Figure 15
Structures of the second series of pyridinone (compounds 71 and 72) and isoquinoline analogues (compounds 73–78).
Figure 16
Figure 16
Structures of the most active compounds among the isoquinolinone and pyridinone analogues: BI-7271 (compound 73), BI-7273 (compound 75), and BI-9564 (compound 79).
Figure 17
Figure 17
Structures of imidazo[1,5-a]pyrazin-8(7H)-one derivatives (compounds 80–87).
Figure 18
Figure 18
Structures of pyrrole analogs (compounds 88–90).
Figure 19
Figure 19
Structures of 6-methylquinazolin-4(3H)-one analogues (compounds 91–95).
Figure 20
Figure 20
Structures of the 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one analogues (compounds 96–104).
Figure 21
Figure 21
Structures of compounds 105–109.
Figure 22
Figure 22
Structure of compound 110.
Figure 23
Figure 23
Structures of EA-89 (compound 111) and QA-68 (compound 112).
Figure 24
Figure 24
Structures of compounds 113–118.
Figure 25
Figure 25
Structures of compounds 119 and 120.
Figure 26
Figure 26
(A) Structures of compounds 121–126; (B) structures of compounds 127–130; (C) structures of compounds 131–136.
Figure 27
Figure 27
Structures of compounds 137–138.
See this image and copyright information in PMC

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