The US researchers have found an anti-cancer agent, which may prevent the activation of PI3K pathway, resulting in inhibition of cancer cell growth.
The findings indicated that the drug zeroes in on mutated nuclear receptors found in cancer, leaves normal proteins alone.
According to Sanford-Burnham Prebys Medical Discovery Institute researchers, PI3K pathway is common to many cancers, K-80003 - an anti-cancer agent, could have broad therapeutic applications.
Senior author Xaio-kun Zhang said that K-80003 binds specifically to a truncated form of the retinoid X receptor-alpha (tRXRa) protein that promotes tumors.
Zhang added that when it binds tRXRa, it freezes the protein into an inactive (tetrameric) configuration that prevents it from stimulating the PI3K pathway.
"A major goal of this study was to dig deeper and find out why this compound is so effective, and appears to have so few side effects," adds Zhang.
The team used X-ray crystallography to find that six molecules of K-80003 bound to the tetramer interfaces.
The findings showed that K-80003 creates a configuration that locks the tetramer into a tight ball, hiding all of its binding sites so it cannot trigger the PI3K pathway.
RXRa is a nuclear receptor and it has the ability to control gene expression.
These findings also help illustrate how nuclear receptors can function outside the nucleus and how changes in both conformation and location can dramatically alter their function.
In the long-term, understanding these mechanisms could lead to a variety of new therapies.
"The tRXRa protein is produced in almost all cancers. So the compound could be very effective for many different types, such as breast, liver and colon," Zhang added.
Tarrex Biopharma, Inc. has licensed the compound and announced that they will soon begin Phase 1 clinical trials at the Dana Farber Cancer Center for patients with colorectal cancer.
The study appears in journal of Nature Communications.
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