Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates.

Hyperactivation of the P13K/AKT/mTOR signaling pathway is common in cancer, and P13K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of P13K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortinannin (2a) analogues conjugated to rapamycin (3a) analogues viaa prodrug linker are uniquely positioned for this approach. Out- efforts led to the discovery of diester-linked conjugates that, upon in vivo hydrolysis, released two highly potent inhibitors. Conjugate 7c provided enhanced solubility relative to 3a and to an equivalent mixture of 3a and 9a and demonstrated profound activity in U87MG mouse xenografts, achieving an MED of 1.5 mg/kg, following weekly intravenous dosing. At 15 mg/kg, 7c completely inhibited the growth of HT29 tumors, whereas an equivalent mixture of the inhibitors was poorly tolerated. In the A498 renal tumor model, 7c exhibited superior efficacyover3aor9a whenadministered asa singleagentorincombination with bevacizumab. Thus, We have uncovered it novel approach to target both P13K and mTOR via hybrid inhibitors, leading to it broader and more robust anticanccr efficacy.