wortmannin

Wortmannin (SL-2052) is a PI3K inhibitor (IC50=3 nM) that is covalent and irreversible. Wortmannin is also an inhibitor of PlK1 and PlK3 (IC50=5.8/48 nM) that blocks autophagy.

Phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) act synergistically in promoting cancer. Wortmannin is a potent inhibitor of PI3K enzymes, while rapamycin blocks mTOR Complex 1 TORC1. Wortmannin-rapamycin conjugate consists of analogs of 17-hydroxy wortmannin and rapamycin conjugated via a prodrug linker. Hydrolysis of the prodrug linker in vivo releases the inhibitors. The wortmannin-rapamycin conjugate inhibits the growth of HT-29 colon tumors and A498 renal tumors in mice better than rapamycin alone. Also, the conjugate, when given in combination with the VEGF-blocker bevacizumab, produces substantial regression of larger A498 tumors. Finally, the wortmannin-rapamycin conjugate is tolerated better than an equivalent mixture of the inhibitors.

17β-Hydroxywortmannin is an orally active phosphatidylinositol-3-kinase (PI-3-kinase) inhibitor, exhibiting an IC50 of 0.5 nM and notably suppresses osteoclast resorption at an IC50 of 10 nM. Additionally, it demonstrates antitumor activity.

LY-294002 hydrochloride (NSC 697286) is a synthetic molecule inhibitor of PI3Kα δ β (IC50: 0.5 0.57 0.97 μM, in cell-free assays); more stable than Wortmannin in solution, and also is a blocker of autophagosome formation.

SCH79797 dihydrochloride is an effective and selective antagonist of protease activated receptor 1 (PAR1) with an IC50 of 70 nM and a Ki of 35 nM. SCH79797 dihydrochloride has antiproliferative and pro-apoptotic effects.