GSK864 Inhibitor for mutant isocitrate dehydrogenase

This probe is available from Sigma and Cayman Chemical.


GlaxoSmithKline has developed GSK864 [1], a potent and selective inhibitor of mutant IDH1, and has made this available as an SGC chemical probe.  GSK864 inhibits IDH1 mutants R132C/R132H/R132G with IC50 values of 9/15/17 nM, respectively, and is moderately selective over wild-type IDH1 and IDH2 mutants/wild-type. Treatment of R132C IDH1 mutant HT-1080 cells for 24 hours with GSK864 results in a dose-dependent reduction of 2-hydroxyglutarate (2-HG), which is not observed with GSK990, a structurally similar compound which is inactive as an IDH1 inhibitor. GSK864 has been shown to be selective in vitro for IDH1 over other classes of proteins (7TMs, ion channels, kinases) and chemoproteomic studies with GSK321, an analog of GSK864, confirm selective binding of IDH1 by this chemical series.  GSK864 has a pharmacokinetic profile suitable for in vivo studies.

Chemoproteomics: the selectivity of GSK864 for IDH1 was illustrated by conducting a chemoproteomics experiment with a closely related analog, GSK321 [1]. GSK321 was functionalized so that it could be immobilized to NHS-activated Sepharose beads which were then incubated with a lysate (protein concentration 5 mg/mL) from HT-1080 cells. The experimental plan included using GSK990 and vehicle as control bait. The proteins were eluted from the beads and then subjected to in-gel digestion and labelling with TMT reagents. LC/MS/MS identified over 300 proteins of which only one, IDH1 had IC50 < 200 nM. 



(negative control)

Physical and chemical properties for GSK864
Molecular weight560.3
Molecular formulaC30H33FN6O4
No. of chiral centres1
No. of rotatable bonds10
No. of hydrogen bond acceptors8
No. of hydrogen bond donors4
Physical and chemical properties for GSK990 (Negative Control)
Molecular weight429.2
Molecular formulaC23H23N7O2
IUPAC name(7-((1H-imidazol-4-yl)-methyl)-9-((3-methyl-phenylamino)-formyl)-3,7,8-triaza-bicyclo[4.3.0]nona-1(6),8-dien-3-yl)-(1H-pyrrol-2-yl)-methanone
No. of chiral centres0
No. of rotatable bonds7
No. of hydrogen bond acceptors6
No. of hydrogen bond donors3
  • GSK864: Cc1cc(cc(C)c1OC)NC(c1c2CN(C[C@](C)(CON)c2n(Cc2ccc(cc2)F)n1)C(c1ccc[nH]1)=O)=O
  • GSK990: Cc1cccc(c1)NC(c1c2CN(CCc2n(Cc2c[nH]cn2)n1)C(c1ccc[nH]1)=O)=O
  • InChI:
  • GSK864: InChI=1S/C30H33FN6O4/c1-18-12-22(13-19(2)26(18)40-4)34-28(38)25-23-15-36(29(39)24-6-5-11-33-24)16-30(3,17-41-32)27(23)37(35-25)14-20-7-9-21(31)10-8-20/h5-13,33H,14-17,32H2,1-4H3,(H,34,38)/t30-/m1/s1
  • GSK990: InChI=1S/C23H23N7O2/c1-15-4-2-5-16(10-15)27-22(31)21-18-13-29(23(32)19-6-3-8-25-19)9-7-20(18)30(28-21)12-17-11-24-14-26-17/h2-6,8,10-11,14,25H,7,9,12-13H2,1H3,(H,24,26)(H,27,31)
  • InChIKey:


Physical and chemical properties for GSK990 (Negative Control)
Molecular weight501.2
Molecular formulaC28H28FN5O3
IUPAC name(7-(4-fluoro-benzyl)-9-((3-(1-hydroxy-ethyl)-phenylamino)-formyl)-5-methyl-3,7,8-triaza-bicyclo[4.3.0]nona-1(6),8-dien-3-yl)-(1H-pyrrol-2-yl)-methanone
No. of chiral centres2
No. of rotatable bonds8
No. of hydrogen bond acceptors6
No. of hydrogen bond donors3
  • GSK321: C[C@@H](c1cccc(c1)NC(c1c2CN(C[C@@H](C)c2n(Cc2ccc(cc2)F)n1)C(c1ccc[nH]1)=O)=O)O
  • InChI:
  • GSK321: InChI=1S/C28H28FN5O3/c1-17-14-33(28(37)24-7-4-12-30-24)16-23-25(27(36)31-22-6-3-5-20(13-22)18(2)35)32-34(26(17)23)15-19-8-10-21(29)11-9-19/h3-13,17-18,30,35H,14-16H2,1-2H3,(H,31,36)/t17-,18+/m1/s1
  • InChIKey:
selectivity profile
in vitro potency
cell based assay data
  1. UC Okoye-Okafor , B Bartholdy, J Cartier, EN Gao, B Pietrak, etc. (2015) New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nature Chem. Biol. 11: 878–868.
pk properties
co-crystal structures
synthetic schemes
materials and methods