Wortmannin-Rapamycin Conjugate

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.

[H][C@@]12CC[C@H](OC(=O)CCCCCCC(=O)O[C@@H]3CC[C@@H](C[C@@H](C)[C@]4([H])CC(=O)[C@H](C)\C=C(C)/[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C/C=C\C=C(C)/[C@H](C[C@]5([H])CC[C@@H](C)[C@@](O)(O5)C(=O)C(=O)N5CCCC[C@@]5([H])C(=O)O4)OC)C[C@H]3OC)[C@@]1(C)C[C@@H](OC(C)=O)C1=C2C(=O)C(O)=C2\C(=C/N(C)CCCN(C)C)C(=O)O[C@H](COC)[C@]12C |c:46,48,97,t:31,50,103|