Studies on the Mechanism of Phosphatidylinositol 3-Kinase Inhibition by Wortmannin and Related Analogs

Abstract

Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular signaling pathways, structure-activities studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortaminnin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17beta-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.

Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment.

“…It is possible, however, that some of these effects are mediated through inhibition of related kinases. Similarly, there are some data on the use of wortmannin and analogues in the treatment of xenografted tumours in immunodeficient mice (Norman et al 1996). The therapeutic index of the compounds is reported to be low but, again, it is unclear whether this is the consequence of broad-spectrum inhibition of the class I PI3-kinases or results from inhibition of other classes of PI3-kinase and the related kinases.…”

Polymorphism and C-H...O Interaction of Wortmannin, a Phosphatidylinositol 3-Kinase Inhibitor

“…The electron state at this position seems to associate with the reactivity of wortmannin and the C-H ... O hydrogen bond, because no activity for PI 3-kinase and no abnormal short contact have been reported for the C21-methylated analogue. 1 (Received June 29, 1998) (Accepted August 27, 1998)…”

Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

“…55 The first known inhibitor of PI3K, wortmannin, is a furanosteroid derivative isolated from the fungus Penicillium wortmanii, which acts as a potent and irreversible pan-PI3K inhibitor (IC 50 4.2 nM). 56 Unfortunately, this inhibitor also targets other members of the PIKK family and MAPK. Similarly, viridin, a natural steroid derived from Trichoderma viridae, has been shown to inhibit PI3K in a potent and irreversible manner (IC 50 5 nM).…”