ART558 is a potent, selective, low molecular weight allosteric inhibitor of DNA Polθ with an IC50 of 7.9 nM.

 

Brand: BCM

 

Target: DNA/RNA Synthesis

 

Signaling Pathways: Cell Cycle/Checkpoint; DNA Damage/DNA Repair

 

In Vitro: ART558 (5μM; 0~72 hours; BRCA2wild-type or BRCA2‒/‒ cells) shows γH2AX accumulation in cells. ART558 (0~10 μM; 7 days; BRCA2wild-type or BRCA2‒/‒ cells) shows synthetic lethality and a combinatorial effect with the PARPi olaparib in previously described isogenic models of BRCA1-deficiency. ART558 inhibits the major Polθ mediated DNA repair process, Theta-Mediated End Joining, without targeting NonHomologous End Joining. ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. ART558 increases the residence time of YFP-tagged full-length Polθ at sites of laserinduced DNA damage.

 

Boiling Point: 621.9±55.0 °C(Predicted)

 

pKa: 13.58±0.40(Predicted)

 

Solubility: Soluble in DMSO; soluble in Ethanol. Insoluble in Water.

 

GHS: GHS07

 

Isomeric SMILES: CC1=CC(=CC=C1)N(C)C(=O)[C@@H]2[C@@H](CCN2C3=NC(=CC(=C3C#N)C(F)(F)F)C)O  

 

InChIKey: YHMDHAMZFMNMTF-MSOLQXFVSA-N  

 

InChI: InChI=1S/C21H21F3N4O2/c1-12-5-4-6-14(9-12)27(3)20(30)18-17(29)7-8-28(18)19-15(11-25)16(21(22,23)24)10-13(2)26-19/h4-6,9-10,17-18,29H,7-8H2,1-3H3/t17-,18+/m1/s1 

 

Attribute
[Chem Name]	(2S,3R)-1-[3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-hydroxy-N-methyl-N-(3-methylphenyl)pyrrolidine-2-carboxamide
[Synonym]	ART558
[CAS No.]	2603528-97-6
[MDL No.]	MFCD34474085
[Formula]	C21H21F3N4O2
[Molecular]	418.41
[Form]	Solid Powder
[Storage]	Sealed in dry. Stored at -20°C.

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