Combination of kinase inhibitors and uses thereof

The method of any one of the preceding claims, wherein the disease condition associated with PI3-kinase α and/or a RTK is selected from the group consisting of neoplastic condition, autoimmune disease, inflammatory disease, fibrotic disease and kidney disease.

A method of inhibiting phosphorylation of Akt in a cell, comprising contacting a cell with an effective amount of a PI3-kinase α inhibitor and a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits activity of a class I RTK relative to one or more type I phosphatidylinositol 3-kinases (PI3-kinase) as ascertained by a cell-based assay or an in vitro kinase assay, wherein the PI3-kinase α inhibitor exhibits selective inhibition of PI3-kinase α relative to one or more type I phosphatidylinositol 3-kinases (PI3-kinase) ascertained by an in vitro kinase assay, wherein the one or more type I PI3-kinase is selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor selectively inhibits PI3-kinase α relative to all other type I phosphatidylinositol 3-kinases (PI3-kinase) consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 50 nM or less as ascertained in an in vitro kinase assay.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor inhibits PI3-kinase α with an IC50 value of about 20 nM or less as ascertained in an in vitro kinase assay.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is at least 5 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor selectively inhibits PI3-kinase α with an IC50 value that is less than about 200 nM, and said IC50 value is at least 5 times less than its IC50 value against all other type I PI3-kinases selected from the group consisting of PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The method of any one of the preceding claims, wherein the RTK inhibitor binds to and directly inhibits HER2 or EGFR.

The method of any one of the preceding claims, wherein the RTK inhibitor inhibits HER2 or EGFR with an IC50 value of about 100 nM or less as ascertained in an in vitro assay, for example an in vitro kinase assay.

The method of any one of the preceding claims, wherein the RTK inhibitor inhibits HER2 or EGFR with an IC50 value of about 50 nM or less as ascertained in an in vitro assay, for example an in vitro kinase assay.

The method of any one of the preceding claims, wherein the RTK inhibitor inhibits HER2 or EGFR with an IC50 value of about 20 nM or less as ascertained in an in vitro assay, for example an in vitro kinase assay.

The method of any one of the preceding claims, wherein the RTK inhibitor inhibits HER2 or EGFR with an IC50 value of about 50 nM or less as ascertained in an in vitro assay, for example an in vitro kinase assay, and that the RTK inhibitor is substantially inactive against one or more types I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The method of any one of the preceding claims, wherein the RTK inhibitor inhibits both HER2 and EGFR with an IC50 value of about 100 nM or less as ascertained in an in vitro assay, for example an in vitro kinase assay, and said IC50 value is at least 5 times less than its IC50 value against all type I PI3-kinases selected from the group consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor and/or the RTK inhibitor are administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor and/or the RTK inhibitor are co-administered to the subject in the same formulation.

The method of any one of the preceding claims, wherein the PI3-kinase α inhibitor and/or the RTK inhibitor are co-administered to the subject in different formulations.

A pharmaceutical composition comprising a combination of an amount of PI3-kinase α inhibitor and an amount of RTK inhibitor, wherein said combination provides a synergistic therapeutic effect in a subject in need thereof.