Separate PI3K and mTORC1 inhibitors joined by prodrug linker
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.
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