Patent Watch

September 16, 2013

These PI3Kβ inhibitors may be effective against cancer. Inventors R. A. Rivero and R. Tedesco report imidizopyridine derivatives represented by formula 1 that inhibit the PI3 kinases—particularly PI3Kβ—and may be used to treat cancer and other diseases.

The phosphoinositide 3-kinase (PI3K) family consists of 15 proteins that have distinct substrate specificities and modes of regulation. There are several classes of PI3Ks; class 1 PI3Ks have a catalytic subunit known as p110 with four types (isoforms): p110α, p110β, p110γ, and p110δ.

The PI3K signaling pathway is activated in many human cancers, and its importance in carcinogenesis is well established. A study has confirmed a link between the PI3K pathway and cancer. In addition, the results of a study of overexpression imply that the PI3Kβ isoform is necessary for transformations induced by the loss or inactivation of PTEN in vitro and in vivo. PTEN (phosphatase and tensin homologue) is a tumor suppressor gene protein that is frequently mutated or deleted by various human cancers.

Besides carcinogenesis, PTEN deficiency and the corresponding overexpression of PI3K-Akt gene may be related to other disorders such as fibrogenesis, arthritis, nephropathy, and liver cirrhosis. (Akt is protein kinase B.) These findings indicate that PI3K p110β inhibition is a promising target for treating cancer and other diseases related to PTEN loss or deficiency.

General formula and three examples of PI3Kβ inhibitors

The inventors describe the synthesis of eight examples of formula 1 compounds, including 2, 3, and 4 in the figure. They used three assays to evaluate them:

  • homogeneous time-resolved fluorescence (HTRF) energy transfer in vitro profiling assays for PI3K inhibition;
  • inhibition of phosphorylation of Akt in PTEN-deficient tumor cell line MDA-MB-468; and
  • cell growth inhibition in PTEN-deficient cell line MDA-MB-468e.

The biological data from these assays for the three representative examples are shown in the table.

Example HTRF PI3K
pIC50
pAkt MDA-MB-468
IC50 (nM)
Prolif MDA-MB-468
EC50 (nM)
2 8.3 435.86 41
3 8.3 41.4 152.8
4 9 15.88 18.1

(GlaxoSmithKline [Philadelphia]. WIPO Publication 2013095761, June 27, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.