Exploring the Dual Inhibitory Mechanism of Romidepsin (FK228) and Analogs: A New Frontier in HDAC/PI3K Cancer Therapy

Romidepsin, known as FK228, is a medication that has been approved by the FDA for treating specific types of lymphoma. It has been shown to be an effective HDAC inhibitor and also functions as a PI3K inhibitor, making it a dual inhibitor. The combination of HDAC and PI3K inhibitors has been found to synergistically induce cancer cell death, which makes the development of a dual inhibitor like FK228 highly desirable for cancer treatment. Through a process of optimization, the most potent analog, FK-A11, was identified. This analog was found to be particularly effective at inhibiting AKT phosphorylation and promoting histone acetylation, leading to enhanced cytotoxic effects in cancer cells.

The study characterized the properties of FK228 analogs as PI3K inhibitors and found several key points:

FK-A11 competes with ATP for binding to PI3K.
It acts as an inhibitor across all p110 isoforms.
It selectively targets PI3K out of a range of cellular kinases.
The reduction of an internal disulfide bond in FK228 analogs does not affect their PI3K inhibitory activity, in contrast to their HDAC inhibitory activity.
Molecular modeling and binding affinity analysis revealed the structural features that contribute to the potency of PI3K inhibition.

The study's findings support the concept that FK228 analogs can serve as dual HDAC/PI3K inhibitors, which could be instrumental in the development of new cancer therapeutics.