The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer

Abstract

Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

“…To establish whether increased MAPK activity is causative for the loss of ISCs and crypts, we inhibited the downstream MEK1/2 kinases using AZD6244 36 and alternatively the phosphatidylinositol 3 kinase cascade using the specific inhibitor GDC0941. 37 Significantly, MEK inhibition by AZD6244 had a similar protective effect as PLX4720 and supported organoid survival in the presence of doxycycline (Figure 5d). In contrast, inhibition of the phosphatidylinositol 3 kinase cascade by GDC0941 did not rescue organoid survival.…”

A practical drug discovery project at the undergraduate level

“…Thus, intermediate aldehydes 7 23 and 10 24 that are not commercially available were prepared and donated by GSK. The project provides a showcase for two mechanistically important reactions frequently employed in the pharmaceutical industry: reductive amination 25 and the Suzuki-Miyaura reaction 26 for biaryl coupling.…”

“…The project provides a showcase for two mechanistically important reactions frequently employed in the pharmaceutical industry: reductive amination 25 and the Suzuki-Miyaura reaction 26 for biaryl coupling. Preliminary investigations of the chemistry by GSK following the procedures described by Folkes et al 23 revealed some problems. Consequently, in order to give the best chance for many analogues to be completed, the students are provided with modified reaction procedures, and are not encouraged to vary them.…”

“…Amines 8n and 8o were purchased as their N-Boc derivatives. Compounds 7 and 10 were prepared by GSK according to the methods of Folkes et al 23 Palladium catalysts 12 and 13 were purchased from Sigma-Aldrich and Alfa Aesar, respectively. Column chromatography was performed on silica gel or aminopropyl-modified silica gel (Biotage Isolute or SNAP cartridges) with a Jones Chromatography Flashmaster II automated system.…”

“…Incorporation of this heterocycle into further derivatives would permit a search for more potency through more lipophilic amines, without departing from the ideal logD range or increasing the molecular weight beyond 500, as has recently been described by Genentech-Piramed. 29 It is interesting that, as yet, none of the students have proposed making GDC-0941 ( Figure 6), 23 which was the PI3K inhibitor taken into development. This is because the sulfonylpiperazine does little to improve aqueous solubility and is thus an unattractive choice of amine.…”