PI3K/Akt/mTOR pathway: a potential target in rheumatoid arthritis?
Exploring the possibility of inducing cell death in rheumatoid arthritis by targeting the “survival” pathway
Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disease of synovial joints. Pro-inflammatory cytokines, chemokines and adhesion molecules which are elevated in the RA synovial joint also affect other organ systems, including most prominently, the cardiovascular system. At the cell and molecular level, RA is characterized by dysfunctional innate and adaptive immunity. Thus, inflammation causes the destruction of articular cartilage and the erosion of subchondral bone leading to a major loss of joint function. Although developing anti-cytokine biologic drugs, other agents that reduce T-cell and B-cell hyperactivity and a small molecule inhibitor (SMI) that selectively inhibits Janus kinase-3 will alter the long-term clinical course of RA, there continues to be a critical need for novel RA drug development.
The pathology of RA stems from the loss of those cellular functions which regulate the balance between cell proliferation and cell death. In that regard, the PI3K/Akt/mTOR signal transduction or “survival” pathway has recently entered the forefront of RA research. I just reviewed the development of novel SMIs for the PI3K/Akt/mTOR pathway1 in which I asserted that PI3K/Akt/mTOR drug development program for RA used paradigms from research on cancer cells. Although selective SMIs for PI3K are a target for drug development, significant advances in acknowledging that themTORC1/mTORC2 subunits are the critical regulators of cell survival has focused attention on developing mTOR inhibitors. Thus, the SMI, PP442 is a highly sensitive mTORC1/mTORC2 kinase inhibitor (IC50, 8nM). However, a few dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are also in various stages of drug development. From all of the available evidence to date, there is every reason to conclude that these and perhaps other PI3K/mTOR inhibitors will eventually reach the clinic for the treatment of RA.
1Malemud CJ: The PI3K/Akt/mTOR pathway: a fruitful target for inducing cell death in rheumatoid arthritis? Future Medicinal Chemistry 2015; 7(9): 1137-1147.
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