BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors used for the treatment of cancer, with encouraging results in endocrine resistant breast cancer. Now, BKM120 has been also shown to act as a microtubule disrupting agent.
In a recent study published in Nature Comm. following a multidisciplinary approach combining cell biology, synthetic chemistry and structural biology, two new drugs have been designed that differ from BKM120 by only one Dalton. In spite of the small size differences, the authors were able to separate the dual-activity of BKM120 into discrete PI3K and tubulin inhibitors. Dr. Fernando Díaz, from CIB, contributed to this study by performing the biochemical evaluation of the influence of the drugs in tubulin.
Analysis of the effects of the compounds on cellular growth and microtubule dynamics suggests that the anti-proliferative activity of BKM120 is mainly due to microtubule-disruption rather than through inhibition of PI3K.
The results provide a novel mechanistic basis for next generation PI3K inhibitors with improved safety profiles and flexibility for its use in combination therapies.