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

• Published in: Journal of medicinal chemistry Vol. 53; no. 1; pp. 452 - 459
• Main Authors: Ayral-Kaloustian, Semiramis, Gu, Jianxin, Lucas, Judy, Cinque, Michael, Gaydos, Christine, Zask, Arie, Chaudhary, Inder, Wang, Jianyao, Di, Li, Young, Mairead, Ruppen, Mark, Mansour, Tarek S, Gibbons, James J, Yu, Ker
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.01.2010; Amer Chemical Soc
• Subjects: Androstadienes - chemical synthesis; Androstadienes - chemistry; Androstadienes - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Drug Design; Drug Stability; General aspects; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kidney Neoplasms - drug therapy; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Nude; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - metabolism; Rats; Science & Technology; Sirolimus - chemical synthesis; Sirolimus - chemistry; Sirolimus - pharmacology; Stereoisomerism; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; AKT; KINASE; GROWTH; Antineoplastic agent; Human; Sirolimus; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Rodentia; Glioblastoma; Macrolide; Biological activity; 1-Phosphatidylinositol 3-kinase; Hydrolysis resistance; Signal transduction; Vertebrata; Mammalia; Cell line; Mouse; Animal; Mammalian target of rapamycin; Inhibitor; Colon; Conjugated compound; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901427g

Hyperactivation of the PI3K/AKT/mTOR signaling pathway is common in cancer, and PI3K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of PI3K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortmannin (2a) analogues conjugated to rapamycin (3a) analogues via a prodrug linker are uniquely positioned for this approach. Our 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 efficacy over 3a or 9a when administered as a single agent or in combination with bevacizumab. Thus, we have uncovered a novel approach to target both PI3K and mTOR via hybrid inhibitors, leading to a broader and more robust anticancer efficacy.