GDC-0941, A NOVEL PI3K INHIBITOR

by Selleckchem | Oct 12 2012

GDC-0941
As is known, there have been several identified PI3 kinases, which are divided into classes IA, 1B, II, and III according to the differences of sequence homology and substrate preference. Besides, the PI3K superfamily also includes the Class IV PIK related enzyme family of protein kinases including mTOR, ATM, ATR, and DNA-PK. Of which, Class IA PI3K is a heterodimer composed of a p110 catalytic subunit and a p85 regulatory subunit, and there are three variants of the p110 catalytic subunit designated p110α, β, or δ catalytic subunit. [1] PI3 Kinase is an oncogene that is commonly mutated in cancer. Hence inhibition of PI3K, and in particular p110α, is a promising target for cancer treatment.
To date, there are several inhibitors of PI3K, which have been found and shown good inhibitory activities. GDC-0941 is a thieno[3,2-d]pyrimidine derivatives and is confirmed to be a potent, selective, orally bioavailable inhibitor of class I PI3 Kinase in preclinical studies. [2]

MECHANISM OF GDC-0941 ACTION

In preclinical studies, GDC-0941 shows potent inhibition effects against p110α activity and cancer cell proliferation. Moreover, GDC-0941 leads to cell cycle arrest and apoptosis induction in some human tumor cell lines. GDC-0941 has also demonstrated significant antitumor activity in tumor models. [2] The following mechanism study shows that GDC-0941 binds the ATP-binding pocket of PI3K and prevent formation of the second messenger PIP3 from PIP2, and thus blocks the signal transduction to downstream effectors of PI3K. Some data indicate that GDC-0941 treatment generally decrease levels of phospho-AKT (S473) in the majority of cell lines in a dose-dependent manner, independent of whether a cell line is sensitive or resistant to GDC-0941. Thus, this epitope can be used as one of the predictive biomarkers of sensitivity to the PI3K inhibitor GDC-0941 in breast cancer preclinical models. [3]

CLINICAL TRIALS
On basis of its preclinical activities, GDC-0941 is currently being evaluated in human clinical trials for the treatment of cancer. The safety and tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of GDC-0941 has been evaluated in Phase 1 in Locally Advanced or Metastatic Solid Tumors, including Breast Cancer, and Non-small Cell Lung Cancer. At present, Phase 1 Study of GDC-0973 in combination with GDC-0941 administered in patients with Locally Advanced or Metastatic Solid Tumors is currently recruiting participants. Furthermore, combination study of GDC-0941 and other drugs is in process. Of which, the Phase 2 Study of GDC-0941 in combination with standard doses of chemotherapies or targeted agents, such as carboplatin, paclitaxel and bevacizumab, is currently under way in patients with Non-small Cell Lung Cancer. We will continue to follow up on the new clinical studies about GDC-0941 and the related combination therapy.

REFERENCES
[1] Carpenter CL, et al. Purification and characterization of phosphoinositide 3-kinase from rat liver". J. Biol. Chem. 1990, 265 (32):,19704–19711.
[2] Folkes AJ, et al. 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. J Med Chem. 2008, 51(18), 5522-5532.
[3] O'Brien C, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010, 16(14), 3670-3683.

Cat.No.	Product Name	Information
S1065	Pictilisib (GDC-0941)	Pictilisib (GDC-0941, RG7321) is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM in cell-free assays, with modest selectivity against p110β (11-fold) and p110γ (25-fold). Pictilisib (GDC-0941) induces autophagy and apoptosis. Phase 2.
S1150	Paclitaxel	Paclitaxel is a microtubule polymer stabilizer with IC50 of 0.1 pM in human endothelial cells.Paclitaxel can cause both mitotic arrest and apoptotic cell death. Paclitaxel also induces autophagy.
S1215	Carboplatin	Carboplatin, a derivative of CDDP, is a DNA synthesis inhibitor which binds to DNA, inhibits replication and transcription and induces cell death and interfers with the cell's repair mechanism in A2780, SKOV-3, IGROV-1, and HX62 cells. It induces the formation of DNA interstrand crosslinks and DNA-protein crosslinks. Solutions are unstable and should be fresh-prepared.DMSO is not recommended to dissolve platinum-based drugs, which can easily lead to drug inactivation.