GSK046 (GSK-046, IBET-BD2)

Description

APIM050401: GSK046 (GSK-046, IBET-BD2), is a potent, selective and orally active BD2 bromodomain inhibitor of the BET proteins, with IC₅₀s of 264 nM (BRD2 BD2), 98 nM (BRD3 BD2), 49 nM (BRD4 BD2) and 214 nM (BRDT BD2), respectively.

CAS No.: 2474876-09-8
IUPAC/Chemical Name: 4-acetamido-3-fluoro-N-((1r,4S)-4-hydroxycyclohexyl)-5-((S)-1-phenylethoxy)benzamide
Molecular Formula: C₂₃H₂₇FN₂O₄
Molecular Weight: 414.5
Purity: >99% by achiral and chiral HPLCs
QC: Achiral and Chiral HPLCs, MS, ¹HNMR, and Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Store at 0 °C (short term), -20 °C (long term), Desiccated
Note: Please contact us for COA, Spectra, and SDS information.

Background Information: GSK046 (iBET-BD2) (CAS No.: 2474876-09-8) is a domain-selective and orally active inhibitor of BET with immunomodulatory activity, targeting specifically BDII (Bromodomain II) with IC50s of 264 nM (BRD2 BD2), 98 nM (BRD3 BD2), 49 nM (BRD4 BD2) and 214 nM (BRDT BD2), respectively.[1]

GSK046 (iBET-BD2) and its synthetic analogues were synthesized in 5 steps from commercially available 4-amino-3-hydroxybenzoate (acetylation, alkylation of the phenol, hydrolysis of the methyl amide, and standard amide coupling) [3].

Target: BRD2 BD2, BRD3 BD2, BRD4 BD2, BRDT BD2

IC₅₀: 264 nM (BRD2 BD2), 98 nM (BRD3 BD2), 49 nM (BRD4 BD2), and 214 nM (BRDT BD2)

In Vitro: GSK046 (1000 nM; refresh every three days) reduces the recruitment of BET proteins to interferon (IFN) target genes following IFN-γ stimulation. GSK046 appears to more prominently affect the recruitment of BRD2 and BRD3 compared to BRD4.[1]
GSK046 (0.1-10 μM) displays a more selective phenotypic fingerprint, particularly inhibiting the production of key pro-inflammatory mediators including Th17 cytokines in the B and T cell co-culture system.[1]
GSK046 (0.01-10 μM; 72 hours) does not affect the proliferative activity of human primary CD4+ T cells but still inhibits the production of effector cytokines including IFNγ, IL-17A and IL-22.[1]
GSK046 (0.005-10 μM; 48 hours) impairs macrophage activation following PMA stimulation, without impacting cellular viability.[1]

In Vivo: GSK046 (40 mg/kg/QD; s.c. for 14 days) has immunomodulatory activity.[1]
GSK046 exhibits Cmax (C57BL6 1589, C57B16 2993 ng/mL) and terminal elimination half-lives (C57BL6 1.8, C57B16 1.9 h) following oral administration (C57BL6 10, C57B16 40 mg/kg).[1]
GSK046 exhibits Cmax (mouse 1589, rat 202 ng/mL) and terminal elimination half-lives (mouse 1.8, rat 1.4 h) following oral administration (mouse 10, rat 10 mg/kg).[1]

Do you have any GSK-046 usage recommendations?
In cells: Use at concentrations up to 10 µM. We recommend to test at various concentrations with a 9 point curve starting from 10 µM down in 1/3 serial dilutions.
In vivo: Yes, tested in rat and dog. But GSK620 is the better choice for in vivo studies.

How to make GSK-046 stock solution?
Dissolve in DMSO in the range 10-20 millimolar, make aliquots and store in a -80°C freezer in a microtiter plate or in vials. If the probe does not dissolve readily use gentle heating and/or sonication and/or vortexing. (Please use only 1 freeze/thaw cycle per aliquot.)

Reference:
[1]. Gilan, O. et al. “Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation”, Science 2020, 368, 387-394.
[2]. Seal, J. T. et al. “The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor”, J. Med. Chem. 2020, 63, 9093-9126. (GSK046 (GSK-046, IBET-BD2) and analogues study)
[3]. Preston, A. et al. “Design and Synthesis of a Highly Selective and In Vivo-Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins”, J. Med. Chem. 2020, 63, 9070-9092.
[4]. Yu, Z. et al. “Discovery and Characterization of Bromodomain 2-Specific Inhibitors of BRDT”, Proc. Natl. Acad. Sci. 2021102118.
[5]. Qi, J. et al. “Selective Targeting of Different Bromodomains by Small Molecules”, Cancer Res. 2020, 37, 764-766.
[6]. Harrison, L. A. et al. “Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins”, J. Med. Chem. 2021, 64, 10742-10771.
[7]. Petretich, M. et al. “Domain-selective targeting of BET proteins in cancer and immunological diseases”, Curr. Opin. Chem. Biol. 2020, 57, 184-193.

Frequent questions related to “GSK-046 (GSK046, iBET-BD2) (CAS No.: 2474876-09-8), selective and orally active BD2 bromodomain inhibitor of the BET proteins”:

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Additional information

Size	10 mg, 100 mg, 5 mg, 50 mg

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