Sunday, November 8, 2015

Drugs in Clinical Pipeline: GSK2636771 | PI3K Inhibitor | PI3Kbeta Inhibitor | Cancer Drug

GSK2636771 [2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid] is a potent, orally bioavailable and selective nanomolar inhibitor of the beta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K). GSK2636771 was more selective for PI3Kβ relative to other PI3K class I enzymes (IC50: PI3Kβ = 0.89 nM) with greater than 900-fold selectivity over PI3Kα/PI3Kγ and more than 10-fold over PI3Kδ. It inhibits AKT phosphorylation and downstream signalling measured as decrease of PRAS40-, GSK3β-, and RPS6-phosphorylation in PTEN mutant cell lines [1].

GSK2636771: 2D and 3D Structure

The activity of GSK2636771 is as follows:

IC50 (PI3Kβ enzyme assay) = 0.89 nM

Common Name: GSK2636771
Synonyms: GSK2636771; GSK-2636771; GSK 2636771
IUPAC Name: 2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid
CAS Number: 1372540-25-4
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3Kbeta Inhibitor
Indication: Various Cancers; Anti-Tumor Agents
Development Stage: Phase I/II
Company: GlaxoSmithKline

1H NMR (Estimated) for GSK2626771

1. Arkenau, H. -T.; et. al. Abstract 2514: A phase I/II, first-in-human dose-escalation study of GSK2636771 in patients (pts) with PTEN-deficient advanced tumors. J Clin Oncol  2014, 32, (suppl).
2. Qu, J.; et. al. Benzimidazole derivatives as pi3 kinase inhibitors. WO2012047538A1 (For synthesis and activity see Example 31)