Friday, May 1, 2015

Drugs in Clinical Pipeline: GNE-317

GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] is a dual PI3K/mTOR inhibitor with excellent blood-brain barrier penetration. Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. The compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). 

GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively.

Genentech is developing GNE-317. The efficacy of GNE-317 in 3 intracranial models of Glioblastoma (GBM) suggests that this compound could be effective in the treatment of GBM, either as a single agent or in combination therapy.

Common Name: GNE-317
Synonyms:  GNE-317; GNE 317; GNE317
IUPAC Name: 5-(6-(3-methoxyoxetan-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine
CAS Number: 1394076-92-6
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; mTOR Inhibitor; Dual-Kinase Inhibitor
Indication: Various Cancers; Glioblastomas
Development Stage: Investigational
Company: Genentech Inc.

PI3K and GBM

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cell survival, growth and proliferation. The lipid kinases belonging to the PI3K family phosphorylate the 3'-hydroxyl group of phophatidylinositols, which lead to the activation of the serine/threonine protein kinase Akt. Further downstream effectors include the mTOR complex 1 and S6 kinase. From the 3 classes of PI3K, class Ia is the most widely involved in cancer and its kinases are composed of a catalytic (p110a, p110b, or p110d) and a regulatory subunit (p85 or p55). The phophatase PTEN acts as a tumor suppressor and inhibits PI3K pathway signaling.

PI3K deregulation, through activating mutations of the p110a catalytic subunit or suppression of PTEN, has been associated with the development of numerous cancers. More specifically, alteration of this pathway has been detected in more than 80% of glioblastoma (GBM). GBM is the most common and aggressive primary tumor of the central nervous system (CNS) in adults. This high grade glioma, characterized by rapid growth and diffuse invasiveness, presents very few treatment options. Tumor progression is controlled only for a limited time with a median survival duration of less than 2 years after initial diagnosis. Key signaling proteins of the PI3K pathway are mutated in a large proportion of GBM, leading to persistent activation of the pathway; EGFR amplification and/or mutation, mutation of the PI3K catalytic and regulatory subunits, and loss of PTEN protein are detected in 45%, 10%, and 50% of GBM, respectively. Thus, targeting the PI3K pathway represents an attractive therapeutic approach for brain tumors.

Inhibitors of mTOR, a key mediator of PI3K signaling, have been evaluated in Phase I and II clinical trials as single agents or in combination with receptor tyrosine kinase inhibitors with limited success. These compounds, analogues of rapamycin, mostly target mTORC1. This in turn can trigger a feedback loop, possibly through mTORC2, which results in the activation of Akt. The disappointing results with rapalogues may also be attributed to the failure of the drugs to fully access their target. These 2 points underscore the potential improvement in activity that could be achieved with dual PI3K/mTOR inhibitors (mTORC1 and mTORC2) as well as the challenge in crossing the blood-brain barrier (BBB) and overcoming the protective effect of efflux transporters to reach the brain and tumors with anticancer agents [1].

GNE-317 and GBM

The marked inhibition of the PI3K pathway in the brain of mice with intact BBB, evidenced by the significant suppression of the PI3K and mTOR markers pAkt, p4EBP1, and pS6, suggested that GNE-317 could be efficacious in intracranial tumors driven by activation of this pathway. Studies in the U87 and GS2 orthotopic models of GBM showed that GNE-317 could reduce tumor volumes by 90% and 50%, respectively [1].

1. Salphati, L.; Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. Clin Cancer Res 2012, 18(22), 6239-6248.