GDC-0941

GDC-0941 is a novel selective class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Activation of PI3K/Akt signaling pathway is frequently associated with tumorigenesis. Deregulation of this pathway occurs frequently with a variety of cancers and may contribute to the resistance to many anticancer agents. [1] Developing novel small molecules that specifically block the PI3K/Akt pathway may inhibit tumor growth. GDC-0941 is designed to bind the ATP-binding pocket of PI3K and to prevent formation of phosphatidylinositol-3, 4, 5-triphosphate (PIP3), a second messenger that transmits PI3K downstream signals. [2, 3] It binds to PI3K in an ATP-competitive manner.

GDC-0941 is a potent small-molecule thieno [3, 2-d] pyrimidine inhibitor of the class I PI3K. It is highly selective against isoforms p110( and p110( with IC50 of 3 nM, and moderately selective against isoforms p110( and p110( with IC50s of 33 nM and 75 nM, respectively.

GDC-0941 inhibits cell proliferation in vitro and in vivo. It causes growth inhibition in a variety of cancer cell lines, including A2780, MDA-MB-361, PC3, and U87MG. [2] It also inhibits the growth of trastuzumab–sensitive and –resistant HER2-amplied cancer cells which harbor p110( mutations or PTEN loss. [4] GDC-0941 also reduces tumor volume in different xenograft models. [4]

GDC-0941 can be taken orally.

References:
[1]Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497-5510.
[2]Folkes AJ, Ahmadi K, Alderton WK, 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: 5522-5532.
[3]Knight ZA, Shokat KM. Chemically targeting the PI3K family. Biochem Soc Trans. 2007; 35: 245-249.
[4]Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Br J Cancer. 2011; 104(7): 1116-25.

Ellagic Acid Enhances the Efficacy of PI3K Inhibitor GDC-0941 in Breast Cancer Cells.[Pubmed:25941816]

Curr Mol Med. 2015;15(5):478-86.

The fact that the phosphatidylinositol 3 kinase (PI3K) signaling pathway is one of the most frequently deregulated signaling networks has triggered intensive efforts in the development of PI3K pathway inhibitors. However, recent clinical trial data have shown only limited activity of PI3K inhibitors at tolerated doses. Thus, there is an urgent need to identify rational combination therapy to improve the efficacy of PI3K-targeted cancer treatment. In this study, we investigated if dietary compound ellagic acid (EA) could improve the therapeutic efficacy of PI3K inhibitor GDC-0941 in breast cancer. Specifically, using a panel of breast cancer cell lines, we showed that combined use of EA and GDC-0941 significantly inhibited cell growth under attached and detached conditions, blocked migration and invasion in vitro as well as tumor initiation and metastasis in vivo. Furthermore, we found that EA promoted apoptosis and further reduced AKT/mTOR activation in GDC-0941- treated breast cancer cells. Together, our data suggest that EA may be a safe and effective agent to boost the efficacy of PI3K-directed breast cancer therapy and that such drug combination may merit further clinical investigation.

Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer.[Pubmed:27565810]

Invest New Drugs. 2017 Feb;35(1):37-46.

Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340 mg/day of pictilisib was administered in combination with CP + BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340 mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260 mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340 mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed.

The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells: resistance reversal with WNT inhibitor.[Pubmed:25857298]

Oncotarget. 2015 May 10;6(13):11061-73.

The pan-PI3K inhibitors are one treatment option for triple-negative breast cancer (TNBC). However, this treatment is ineffective for unknown reasons. Here, we report that aberrant expression of wingless-type MMTV integration site family (WNT) and activated WNT signals, which crosstalk with the PI3K-AKT-mTOR signaling pathway through GSK3beta, plays the most critical role in resistance to pan-PI3K inhibitors in TNBC cells. GDC-0941 is a pan-PI3K inhibitor that activates the WNT/beta-catenin pathway in TNBC cells through stimulation of WNT secretion. GDC-0941-triggered WNT/beta-catenin pathway activation was observed in MDA-MB-231 and HCC1937 cells, which are TNBC cell lines showing aberrant WNT/beta-catenin activation, and not in SKBR3 and MCF7 cells. This observation is further investigated in vivo. GDC-0941 exhibited minimal tumor inhibition in MDA-MB-231 cells, but it significantly suppressed tumor growth in HER-positive SK-BR3 cells. In vivo mechanism study revealed the activation of WNT/beta-catenin pathway by GDC-0941. A synergistic effect was observed when combined treatment with GDC-0941 and the WNT inhibitor LGK974 at low concentrations in MDA-MB-231 cells. These findings indicated that WNT pathway activation conferred resistance in TNBC cells treated with GDC-0941. This resistance may be further circumvented through combined treatment with pan-PI3K and WNT inhibitors. Future clinical trials of these two inhibitors are warranted.

The PI3K inhibitor GDC-0941 enhances radiosensitization and reduces chemoresistance to temozolomide in GBM cell lines.[Pubmed:28147244]

Neuroscience. 2017 Mar 27;346:298-308.

Glioblastoma multiforme (GBM) is among the most lethal of all human tumors. It is the most frequently occurring malignant primary brain tumor in adults. The current standard of care (SOC) for GBM is initial surgical resection followed by treatment with a combination of temozolomide (TMZ) and ionizing radiation (IR). However, GBM has a dismal prognosis, and survivors have compromised quality of life owing to the adverse effects of radiation. GBM is characterized by overt activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. GDC-0941 is a highly specific PI3K inhibitor with promising anti-tumor activity in human solid tumors. It is being evaluated in Phase II clinical trials for the treatment of breast and non-squamous cell lung cancer. We hypothesized that GDC-0941 may act as an antitumor agent and potentiate the effects of TMZ and IR. In this study, GDC-0941 alone induced cytotoxicity and pro-apoptotic effects. Moreover, combined with the standard GBM therapy (TMZ and IR), it suppressed cell viability, showed enhanced pro-apoptotic effects, augmented autophagy response, and attenuated migratory/invasive capacity in three glioma cell lines. Protein microarray analyses showed that treatment with TMZ+GDC-0941+IR induced higher levels of p53 and glycogen synthase kinase 3-beta (GSK3-beta) expression in SHG44GBM cells than those induced by other treatments. This was verified in all cell lines by western blot analysis. Furthermore, the combination of TMZ and GDC-0941 with or without IR reduced the levels of p-AKT and O(6)-methylguanine DNA methyltransferase (MGMT) in T98G cells. The results of this study suggest that the combination of TMZ, IR, and GDC-0941 is a promising choice for future treatments of GBM.

Pictilisib (GDC-0941) is a potent inhibitor of PI3Kα/δ with an IC50 of 3 nM, with modest selectivity against p110β (11-fold) and p110γ (25-fold).

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