Name: GSK-699
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

IUPACName

4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxopyridazin-4-yl)amino]-1-methylpiperidin-3-yl]-N-[3-[4-[3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxypropyl]-N-methylanilino]propyl]-N-methylbenzamide

Synonyms

GSK699; GSK 699; 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)-N-(3-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)propyl)phenyl)(methyl)amino)propyl)-N-methylbenzamide; Benzamide, 4-[(3R,5R)-5-[(5-bromo-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl)amino]-1-methyl-3-piperidinyl]-N-[3-[[4-[3-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]oxy]propyl]phenyl]methylamino]propyl]-N-methyl-; 4-[(3R,5R)-5-[(5-Bromo-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl)amino]-1-methyl-3-piperidinyl]-N-[3-[[4-[3-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]oxy]propyl]phenyl]methylamino]propyl]-N-methylbenzamide

Density

1.43±0.1 g/cm3

InChI Key

SARLMRHJAJBYBI-CIDUPMPKSA-N

InChI

InChI=1S/C45H51BrN8O7/c1-50-26-31(24-32(27-50)48-35-25-47-53(4)45(60)40(35)46)29-13-15-30(16-14-29)42(57)52(3)22-7-21-51(2)33-17-11-28(12-18-33)8-6-23-61-37-10-5-9-34-39(37)44(59)54(43(34)58)36-19-20-38(55)49-41(36)56/h5,9-18,25,31-32,36,48H,6-8,19-24,26-27H2,1-4H3,(H,49,55,56)/t31-,32+,36?/m0/s1

SMILES

CN1CC(CC(C1)NC2=C(C(=O)N(N=C2)C)Br)C3=CC=C(C=C3)C(=O)N(C)CCCN(C)C4=CC=C(C=C4)CCCOC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O

Mechanism

Target: GSK-699 targets KAT2A/GCN5 and KAT2B/PCAF histone acetyltransferases.

Binding site: Its acetyltransferase ligand engages the catalytic HAT domain substrate-binding region.

Mechanism of action: GSK-699 is a cell-penetrant CRBN-recruiting PROTAC degrader of KAT2A/B acetyltransferase family members. The molecule links a GCN5/PCAF-directed ligand to a cereblon ligand, enabling recruitment of KAT2A, KAT2B, PCAF, and GCN5 to CRL4CRBN ubiquitin ligase machinery. Productive ternary-complex formation promotes proteasome-dependent degradation and reduces SAGA-associated histone acetyltransferase activity, including decreased H3K9ac levels. GSK-699 is useful for studying acetyltransferase-dependent transcription, chromatin regulation, inflammatory signaling, and degradation-based modulation of SAGA complex enzymatic function.

Applications

• PROTAC-Driven Oncology Research: GSK-699 serves as a valuable tool in cancer research by facilitating the targeted degradation of oncogenic proteins. This PROTAC enables researchers to explore the therapeutic potential of selectively degrading proteins implicated in tumor growth and survival, providing insights into novel cancer treatment strategies.

• Targeted Degradation in Neurodegenerative Disease: By employing GSK-699, scientists can investigate the degradation of proteins associated with neurodegenerative disorders. This application allows for the study of mechanisms underlying protein aggregation and toxicity, offering new avenues for therapeutic intervention in diseases such as Alzheimer's and Parkinson's.

• Signal Transduction Pathway Analysis: GSK-699 is instrumental in dissecting signaling pathways by enabling the targeted degradation of key signaling proteins. Researchers can use this PROTAC to elucidate the roles of specific proteins in cellular signaling, thereby advancing our understanding of complex biological processes and disease mechanisms.

• Drug Resistance Mechanism Studies: Utilizing GSK-699, researchers can examine the degradation of proteins involved in drug resistance. This application aids in identifying potential therapeutic targets and understanding resistance mechanisms, ultimately contributing to the development of more effective treatment strategies in various diseases.

1. Modulating PCAF/GCN5 immune cell function through a PROTAC approach.

Bassi, Z.I. ACS Chem. Biol. 13, 2862-2867 (2018).

P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells. However, by generating the first PCAF/GCN5 proteolysis targeting chimera (PROTAC), we identify small molecules able to degrade PCAF/GCN5 and to potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells. Our data illustrate the power of the PROTAC approach in the context of multidomain proteins, revealing a novel anti-inflammatory therapeutic opportunity for targeting PCAF/GCN5.

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