GSK2636771

Preparation Method

Biochemical selectivity of GSK2636771 was tested using the PI3-Kinase HTRF Assay, as well as the entire panel of GSK in-house kinase selectivity assays. Affinity-enrichment-based chemoproteomics using kinobeads was performed. Briefly, 14 lipid and atypical kinases were enriched from a standard mixture of extracts derived from HeLa, K562, and Jurkat cells using a compound-derivatized bead matrix. The enriched proteins were identified by quantitative mass spectrometry analysis, enabling the simultaneous assessment of binding specificity, and potency for all detected affinity-captured proteins.

Applications

GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ with an apparent Ki value of 0.89 nmol/L (IC50 = 5.2 nmol/L), >900-fold selectivity over p110α and p110γ, and >10-fold selectivity over p110δ isoforms, while sparing other PI3K superfamily kinases.

Cell lines

PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines

Preparation Method

Cell viability was determined after 72 hours of treatment with indicated concentrations of the p110β selective inhibitors GSK2636771 and AZD6482 in 3 p110β-reliant breast and prostate cancer cell lines, 7 PTEN wild-type EEC cells, and 17 PTEN-mutant EEC cells.

Reaction Conditions

1-10uM GSK2636771 for 72 hours

Applications

Upon 72 hours treatment with the p110β inhibitors GSK2636771 and AZD6482, cell viability was significantly more decreased in the control cells [ p110β-reliant PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines] than in PTEN-mutant and PTEN wild-type EEC cells.

Animal models

Female athymic nude mice (4-5-week-old)

Preparation Method

Female athymic nude mice were injected subcutaneously with ZR75-1/FR cells resuspended in matrigel. On the same date, mice were implanted subcutaneously with a 17β-estradiol pellet, and fulvestrant treatment was initiated. Four weeks after implantation, tumor-bearing mice were randomized to treatment with vehicle, GSK2636771 (30 mg/kg/d, orally), BYL719, or the combination, all with a fulvestrant treatment backbone.

Dosage form

GSK2636771 (30 mg/kg/d, orally)

Applications

Inhibition of ER/p110β or ER/p110α/βby GSK2636771 induced rapid tumor regression, whereas ER/p110α inhibition had no significant early effect on growth compared to continued ER inhibition alone.

References:

[1]. Mateo J, Ganji G, et,al . A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017 Oct 1;23(19):5981-5992. doi: 10.1158/1078-0432.CCR-17-0725. Epub 2017 Jun 23. PMID: 28645941.

[2]. Weigelt B, Warne PH, et,al. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3533-44. doi: 10.1158/1078-0432.CCR-12-3815. Epub 2013 May 14. PMID: 23674493; PMCID: PMC3700760.

[3]. Hosford SR, Dillon LM, et,al . Combined Inhibition of Both p110α and p110β Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer. Clin Cancer Res. 2017 Jun 1;23(11):2795-2805. doi: 10.1158/1078-0432.CCR-15-2764. Epub 2016 Nov 30. PMID: 27903677; PMCID: PMC5449270.