NMS-P118 - CAS 1262417-51-5
Catalog number: 1262417-51-5
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C20H24F3N3O2
Molecular Weight:
395.42
COA:
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Targets:
PARP
Description:
NMS-P118 is a highly selective Poly(ADP-ribose) Polymerase 1 (PARP-1) inhibitor with excellent ADME, pharmacokinetic profiles and high efficacy in vivo originated by Nerviano Medical Sciences. It was found to be less myelotoxic in vitro than olaparib which is a dual PARP-1/-2 inhibitor. It was in preclinical trials for Breast cancer, but no development had been published yet.
Purity:
98%
Appearance:
Powder
Synonyms:
2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide
Solubility:
Soluble in DMSO
Storage:
-20°C Freezer
MSDS:
Inquire
Application:
Breast cancer
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
Quantity:
Milligrams-Grams
InChI:
InChI=1S/C20H24F3N3O2/c21-13-9-12-11-26(19(28)17(12)16(10-13)18(24)27)15-3-7-25(8-4-15)14-1-5-20(22,23)6-2-14/h9-10,14-15H,1-8,11H2,(H2,24,27)
Canonical SMILES:
FC(CC1)(F)CCC1N(CC2)CCC2N(C3=O)CC4=C3C(C(N)=O)=CC(F)=C4
Current Developer:
Originator: Nerviano Medical Sciences
1.Free energy calculation provides insight into the action mechanism of selective PARP-1 inhibitor.
Cao R J Mol Model. 2016 Apr;22(4):74. doi: 10.1007/s00894-016-2952-x. Epub 2016 Mar 12.
Selective poly (ADP-ribose) polymerase (PARP)-1 inhibitor represents promising therapy against cancers with a good balance between efficacy and safety. Owing to the conserved structure between PARP-1 and PARP-2, most of the clinical and experimental drugs show equivalent inhibition against both targets. Most recently, it's disclosed a highly selective PARP-1 inhibitor (NMS-P118) with promising pharmacokinetic properties. Herein, we combined molecular simulation with free energy calculation to gain insights into the selective mechanism of NMS-P118. Our results suggest the reduction of binding affinity for PARP-2 is attributed to the unfavorable conformational change of protein, which is accompanied by a significant energy penalty. Alanine-scanning mutagenesis study further reveals the important role for a tyrosine residue of donor loop (Tyr889(PARP-1) and Tyr455(PARP-2)) in contributing to the ligand selectivity. Retrospective structural analysis indicates the ligand-induced movement of Tyr455(PARP-2) disrupts the intra-molecule hydrogen bonding network, which partially accounts for the "high-energy" protein conformation in the presence of NMS-P118. Interestingly, such effect isn't observed in other non-selective PARP inhibitors including BMN673 and A861695, which validates the computational prediction.
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