GSK864

Allosteric of IDH1 (Mutant:R132C, R132H, R132G)

Structure

Information

  • IDH1 (Mutant:R132C, R132H, R132G)
  • Allosteric
  • 50 nM - 1 uM

In Vitro Validations

Uniprot ID: O75874
Target Class: Metabolic enzyme
Target SubClass: Dehydrogenase
Potency: IC 50
Potency Value: 15 nM R132H
Potency Assay: NADPH production and thermal shift assay
PDB ID for probe-target interaction (3D structure): 5DE1
Target aliases:
Isocitrate dehydrogenase [NADP] cytoplasmic, PICD, ...

DOI Reference: 10.1038/nchembio.1930

Uniprot ID: O75874
Target Class: Metabolic enzyme
Target SubClass: Dehydrogenase
Potency: IC 50
Potency Value: 8.8 nM R132C
Potency Assay: NADPH production and thermal shift assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Isocitrate dehydrogenase [NADP] cytoplasmic, PICD, ...

DOI Reference: 10.1038/nchembio.1930

Uniprot ID: O75874
Target Class: Metabolic enzyme
Target SubClass: Dehydrogenase
Potency: IC 50
Potency Value: 16.6 nM R132G
Potency Assay: NADPH production and thermal shift assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Isocitrate dehydrogenase [NADP] cytoplasmic, PICD, ...

DOI Reference: 10.1038/nchembio.1930

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 wild-type IDH1 466.5 nM, R140Q IDH2 1916 nM, R172S IDH2 997 nM, wild-type IDH2 1360 nM
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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This small molecule and its inactive analog, GSK990, are early-stage probe candidates for studying the inhibition of mutant IDH1 in cancer. Further biochemical profiling needs to be completed to better understand the other intracellular targets of GSK864.

(last updated: 29 May 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The selectivity of GSK864 for IDH1 was illustrated by conducting a chemoproteomics experiment with a closely related analog, GSK321 [PMID: 26436839]. 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. 

(last updated: 10 Sept 2016 )

SERP Comments:

GSK864 is an allosteric inhibitor of mutant IDH1, with moderate selectivity versus wild-type IDH1 and IDH2. GSK864 dose-dependently reduces levels of intracellular levels of 2-HG both in vitro and in vivo in a xenograft model. The binding mode of an analog, GSK321, bound to mutant IDH1 was determined by crystallographically, revealing that it binds an allosteric site. GSK321 appears to lock the enzyme in an inactive conformation.

(last updated: 12 Sept 2016 )

Portal Comments

In a 2023 study, Hu et al. evaluated GSK-864 in live-cell assays for Phospholipidosis induction, cautioning about adverse effects at concentrations near 1 uM. (DOI:10.1016/j.chembiol.2023.09.003)

(last updated: 7 Nov 2023)