GSK481

• CAT Number: I002085
• CAS Number: 1622849-58-4
• Molecular Formula: C21H19N3O4
• Molecular Weight: 377.4
• Purity: ≥95%
• Synonyms: GSK481; GSK 481; GSK-481; (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide
• Target: TNF-α
• Solubility: DMSO ≥ 35 mg/mL
• Storage: Store at -20°C
• InChI: InChI=1S/C21H19N3O4/c1-24-18-9-5-6-10-19(18)27-13-17(21(24)26)22-20(25)16-12-15(28-23-16)11-14-7-3-2-4-8-14/h2-10,12,17H,11,13H2,1H3,(H,22,25)/t17-/m0/s1
• InChIKey: KNOUWGGQMADIBV-KRWDZBQOSA-N
• SMILES: O=C(C1=NOC(CC2=CC=CC=C2)=C1)N[C@@H](COC(C=CC=C3)=C3N4C)C4=OO=C(C1=NOC(CC2=CC=CC=C2)=C1)N[C@@H](COC(C=CC=C3)=C3N4C)C4=O

GSK481(CAT: I002085) is an inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIP1 or RIPK1) that blocks autophosphorylation of Ser166 on wild-type human RIP1 with an IC50 value of 2.8 nM. It is selective for RIP1 over a panel of over 450 other kinases, including RIP3. GSK481 inhibits RIP1 from humans and cynomolgus monkeys but is at least 100-fold less potent against non-primate RIP1.

Reference

1. J Med Chem. 2016 Mar 10;59(5):2163-78. doi: 10.1021/acs.jmedchem.5b01898. Epub
2016 Feb 23.
DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly
Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.
Harris PA, King BW, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox
JA, Dare L, Dong X, Finger JN, Grady LC(1), Hoffman SJ, Jeong JU, Kang J,
Kasparcova V, Lakdawala AS, Lehr R, McNulty DE, Nagilla R, Ouellette MT, Pao CS,
Rendina AR, Schaeffer MC, Summerfield JD(1), Swift BA, Totoritis RD, Ward P,
Zhang A(2), Zhang D, Marquis RW, Bertin J, Gough PJ.
Author information:
(1)Platform Technology & Science, GlaxoSmithKline , Winter Street, Waltham,
Massachusetts 02451, United States.
(2)Platform Technology & Science, GlaxoSmithKline , King of Prussia, Pennsylvania
19406, United States.
The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase
in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as
a highly promising target for the treatment of multiple inflammatory diseases. We
screened RIP1 against GSK/’s DNA-encoded small-molecule libraries and identified a
novel highly potent benzoxazepinone inhibitor series. We demonstrate that this
template possesses complete monokinase selectivity for RIP1 plus unique species
selectivity for primate versus nonprimate RIP1. We elucidate the conformation of
RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity
and design specific mutations in murine RIP1 to restore potency to levels similar
to primate RIP1. This series differentiates itself from known RIP1 inhibitors in
combining high potency and kinase selectivity with good pharmacokinetic profiles
in rodents. The favorable developability profile of this benzoxazepinone
template, as exemplified by compound 14 (GSK/’481), makes it an excellent starting
point for further optimization into a RIP1 clinical candidate.