Ludwig Institute for Cancer Research Limited

Masato Kasuga

Michael Derek Waterfield

Ian D Hiles

Ivan Tarasovich Gout

Ritu Bala Dhand

Michael J Fry

Kazuyoshi Yonezawa

George Panayotou

Peter End

The invention provides for a method to inhibit the binding between the p85 and p110 subunits of said PI3-kinase and thus a method to modulate PI3-kinase activity and modulate the response of cells to external stimuli. In particular, disabling, by conventional means, residues located in the inter-SH2 domain of said p85 subunit, specifically a region containing amino acid residue 478 to amino acid residue 513 of p85.alpha. subunit, or amino acid residue 445 to amino acid residue 485 of p85.beta. subunit of said PI3-kinase. Interference with these binding regions will affect binding between the subunits and results in inhibiting PI3-kinase activity. This invention further relates to a methods to modulate the serine kinase activity of the PI3-kinase which can be achieved by disabling the DRHNSN sequence of the p110 subunit and can also be used to effect changes in overall PI3-kinase activity. This invention is further related to an (ant)agonist which affects serine kinase activity of PI3-kinase. An agonist is provided which stimulates the phosphorylation of the p85 subunit at the serine residue at position 608, wherein phosphorylation at the serine residue indirectly results in inhibiting PI3-kinase activity.

Methods to inhibit serine kinase activity and to alter intersubunit

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Kobe, Japan

Masato Kasuga