The discovery of GDC-0941: A potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer

LB-146 Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signalling pathway in a wide variety of tumours. The consequences of deregulation of this pathway include tumour progression, proliferation, survival, growth, invasion, angiogenesis and metastasis. PI3K signalling is negatively regulated by the dual phosphatase PTEN, and this is one of the most commonly mutated proteins in human malignancy. In addition, persistent signalling through the PI3K/Akt pathway has been shown to be a major mechanism of resistance to therapy. Hence, PI3K, and in particular the p110α subunit of PI3K, is a highly promising candidate for cancer treatment. This poster describes our medicinal chemistry efforts to optimize a series of thieno[3,2- d ]pyrimidines that demonstrate potent inhibition of PI3K p110α, culminating in the discovery of GDC-0941. The structure of GDC-0941 will be disclosed. This compound is a potent ATP-competitive PI3 kinase inhibitor with an IC50 of 3 nM against the PI3K p110α subunit, and shows potent growth inhibitory activity in vitro in a range of human tumour cell lines. GDC-0941 is efficacious in xenograft models following oral administration, and is currently being evaluated in human clinical trials for the treatment of cancer.