GSK 2837808A

• CAT Number: I011855
• CAS Number: 1445879-21-9
• Molecular Formula: C31H25F2N5O7S
• Molecular Weight: 649.626
• Purity: ≥95%
• Synonyms: 3-[[3-[(Cyclopropylamino)sulfonyl]-7-(2,4-dimethoxy-5-pyrimidinyl)-4-quinolinyl]amino]-5-(3,5-difluorophenoxy)benzoic Acid
• Target: Lactate Dehydrogenase
• Solubility: Soluble in DMSO > 10 mM
• Storage: Store at -20°C
• IUPAC Name: 3-[[3-(cyclopropylsulfamoyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl]amino]-5-(3,5-difluorophenoxy)benzoic acid
• InChI: InChI=1S/C31H25F2N5O7S/c1-43-29-25(14-35-31(37-29)44-2)16-3-6-24-26(9-16)34-15-27(46(41,42)38-20-4-5-20)28(24)36-21-7-17(30(39)40)8-22(13-21)45-23-11-18(32)10-19(33)12-23/h3,6-15,20,38H,4-5H2,1-2H3,(H,34,36)(H,39,40)
• InChIKey: RZBCPMYJIARMGV-UHFFFAOYSA-N
• SMILES: COC1=NC(=NC=C1C2=CC3=NC=C(C(=C3C=C2)NC4=CC(=CC(=C4)C(=O)O)OC5=CC(=CC(=C5)F)F)S(=O)(=O)NC6CC6)OC

GSK2837808A (CAT: I011855) is a potent and selective inhibitor of lactate dehydrogenase A (LDHA) with high affinity. LDHA is an enzyme involved in anaerobic glycolysis, converting pyruvate to lactate. GSK2837808A exhibits remarkable inhibitory activity against LDHA (IC50 = 1.9 nM) compared to LDHB (IC50 = 14 nM). This selective inhibition of LDHA makes GSK2837808A a promising compound for potential therapeutic applications, particularly in cancer metabolism. By blocking LDHA, GSK2837808A disrupts the energy metabolism of cancer cells, offering the potential to inhibit tumor growth. Further research is underway to explore the therapeutic potential of GSK2837808A in cancer treatment.

Reference

1. Biochem Biophys Res Commun. 2017 Apr 15;485(4):742-745. doi:
10.1016/j.bbrc.2017.02.119. Epub 2017 Feb 28.

The inhibition of lactate dehydrogenase A hinders the transcription of histone 2B
gene independently from the block of aerobic glycolysis.

Brighenti E(1), Carnicelli D(1), Brigotti M(2), Fiume L(1).

Author information:
(1)Department of Experimental, Diagnostic and Specialty Medicine, University of
Bologna, Bologna, Italy.
(2)Department of Experimental, Diagnostic and Specialty Medicine, University of
Bologna, Bologna, Italy. Electronic address: .

Most cancer cells use aerobic glycolysis to fuel their growth and many efforts
are made to selectively block this metabolic pathway in cancer cells by
inhibiting lactate dehydrogenase A (LDHA). However, LDHA is a moonlighting
protein which exerts functions also in the nucleus as a factor associated to
transcriptional complexes. Here we found that two small molecules which inhibit
the enzymatic activity of LDHA hinder the transcription of histone 2B gene
independently from the block of aerobic glycolysis. Moreover, we observed that
silencing this gene reduces cell replication, hence suggesting that the
inhibition of LDHA can also affect the proliferation of normal non-glycolysing
dividing cells.

2. Sci Rep. 2017 Jan 20;7:40778. doi: 10.1038/srep40778.

Modification of tumour cell metabolism modulates sensitivity to Chk1
inhibitor-induced DNA damage.

Massey AJ(1).

Author information:
(1)Vernalis Research, Granta Park, Cambridge, CB21 6GB, UK.

Chk1 kinase inhibitors are currently under clinical investigation as potentiators
of cytotoxic chemotherapy and demonstrate potent activity in combination with
anti-metabolite drugs that increase replication stress through the inhibition of
nucleotide or deoxyribonucleotide biosynthesis. Inhibiting other metabolic
pathways critical for the supply of building blocks necessary to support DNA
replication may lead to increased DNA damage and synergy with an inhibitor of
Chk1. A screen of small molecule metabolism modulators identified combinatorial
activity between a Chk1 inhibitor and chloroquine or the LDHA/LDHB inhibitor GSK
2837808A. Compounds, such as 2-deoxyglucose or 6-aminonicotinamide, that reduced
the fraction of cells undergoing active replication rendered tumour cells more
resistant to Chk1 inhibitor-induced DNA damage. Withdrawal of glucose or
glutamine induced G1 and G2/M arrest without increasing DNA damage and reduced
Chk1 expression and activation through autophosphorylation. This suggests the
expression and activation of Chk1 kinase is associated with cells undergoing
active DNA replication. Glutamine starvation rendered tumour cells more resistant
to Chk1 inhibitor-induced DNA damage and reversal of the glutamine starvation
restored the sensitivity of tumour cells to Chk1 inhibitor-induced DNA damage.
Chk1 inhibitors may be a potentially useful therapeutic treatment for patients
whose tumours contain a high fraction of replicating cells.