Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

Abstract

BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.

The PI3K Pathway in Human Disease

“…Enthusiasm for the efficacy data was unfortunately dampened by the frequency of serious adverse events leading to frequent discontinuations in both BELLE trials, with elevation of liver transaminases as a dose-limiting toxicity. Buparlisib has off-target tubulin-binding activity, which prompted the identification of a close analog, PQR309, that is more selective for PI3K (Bohnacker et al, 2017) and is now in early clinical trials.…”

BF12, a Novel Benzofuran, Exhibits Antitumor Activity by Inhibiting Microtubules and the PI3K/Akt/mTOR Signaling Pathway in Human Cervical Cancer Cells

“…Therefore, our results showed that BF12 inhibitors. [33] The compound studied here, BF12, was found to also both inhibit microtubule polymerization, resulting in a blocking of the cell cycle at G2/M phase, and induce apoptosis, by inhibiting the PI3 K/Akt/ mTOR signaling pathway. Our analysis revealed that BF12 could inhibit the PI3 K/Akt/mTOR signaling pathway and microtubules in combination, thereby exerting an inhibitory effect on SiHa and HeLa cells.…”

“…Thomas et al. defined BKM120 as a specific PI3 K and tubulin inhibitors . The compound studied here, BF12, was found to also both inhibit microtubule polymerization, resulting in a blocking of the cell cycle at G2/M phase, and induce apoptosis, by inhibiting the PI3 K/Akt/mTOR signaling pathway.…”

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…These dual inhibitors, in many cases, through their multiple MOAs, have been observed to cause substantially enhanced apoptosis of cancer cells and strongly overcome cancer cell resistance compared with their single inhibitor counterparts . Additionally, numerous tubulin/kinase dual inhibitors have been observed to demonstrate substantially lower toxicities to normal cells with significantly higher maximum tolerated dose (MTD), overcoming one of the major limitations of single‐tubulin inhibitor–based therapeutic agents . In the event of dual inhibition, it is difficult to understand which MOA is responsible for the underlying cell toxicity and cell cycle arrest, given that both kinase and tubulin inhibitors are responsible for either phenotype .…”

“…Buparlisisb ( BKM120, 71 ) is known to be one of the frontline phosphoinositide 3‐kinase (PI3K) inhibitors for the treatment of cancer . However, it is also known to interfere with MT polymerization promoting dual inhibitory MOA.…”