Omipalisib is an investigational drug, known also by its chemical designation GSK2126458. It is a small molecule that inhibits specific cellular pathways, aiming to interfere with disease progression.
How Omipalisib Works
Omipalisib functions as a dual inhibitor of the phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These pathways are intricate signaling networks within cells that regulate many fundamental processes, including cell growth, proliferation, survival, and metabolism. The PI3K pathway, for example, converts PIP2 to PIP3, which activates AKT. Omipalisib interferes with this process by inhibiting PI3K, thereby reducing AKT phosphorylation and disrupting the signaling cascade.
By targeting both PI3K and mTOR, omipalisib aims to broadly suppress these overactive pathways, which are often implicated in various diseases. The inhibition of these pathways can lead to effects such as G1 cell cycle arrest and reduced cell proliferation.
Applications in Cancer Treatment
The PI3K/mTOR pathway is frequently overactive in many types of cancer, promoting uncontrolled cell growth and survival. Omipalisib’s ability to inhibit this pathway makes it a candidate for various cancer treatments. It has shown broad anti-tumor activity in preclinical studies.
Omipalisib has been investigated in phase 1 clinical trials for patients with advanced solid tumors and lymphoma. Durable objective responses have been observed across various tumor types, including sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer. Additionally, omipalisib has shown the ability to sensitize cancer cells to radio- and chemotherapy by suppressing the non-homologous end joining (NHEJ) pathway. This suggests a potential role for omipalisib in combination therapies, though further validation in different human cancer cell lines is needed.
Role in Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease of unknown cause, characterized by the scarring of lung tissue. This scarring leads to a decline in lung function. The PI3K/mTOR pathway is also implicated in the development of IPF.
Omipalisib’s mechanism of inhibiting PI3K/mTOR is thought to be beneficial in IPF by reducing fibrosis and inflammation. Preclinical data indicate that omipalisib can attenuate fibroblast proliferation and collagen synthesis, which are key features of fibrosis. A phase 1 trial in individuals with IPF demonstrated that orally administered omipalisib inhibited the PI3K/mTOR pathway in both the systemic circulation and the lungs. This inhibition also reduced aberrant glucose signaling in fibrotic lung regions, supporting the pathway as a target for new IPF treatments.
Current Research and Safety Profile
Omipalisib has undergone phase 1 clinical trials for both cancer treatment and idiopathic pulmonary fibrosis. These trials have concluded, but omipalisib has not received widespread regulatory approvals, indicating its continued investigational status.
In terms of safety, common adverse events observed in studies include diarrhea, increased blood glucose levels, lymph node pain, nausea, oral pain, rash, and rhinitis. In a phase 1 study for solid tumors, dose-limiting toxicities included grade 3 diarrhea, fatigue, and rash. The maximum tolerated dose (MTD) in this study was 2.5 mg per day. While omipalisib was generally well-tolerated in a short-term dose escalation study for IPF, diarrhea was an anticipated dose-limiting adverse event.