PMID- 19928864
OWN - NLM
STAT- MEDLINE
DCOM- 20100202
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 53
IP  - 1
DP  - 2010 Jan 14
TI  - 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.
PG  - 452-9
LID - 10.1021/jm901427g [doi]
AB  - 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.
FAU - Ayral-Kaloustian, Semiramis
AU  - Ayral-Kaloustian S
AD  - Discovery Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl 
      River, New York 10965, USA. Ayralks@wyeth.com
FAU - Gu, Jianxin
AU  - Gu J
FAU - Lucas, Judy
AU  - Lucas J
FAU - Cinque, Michael
AU  - Cinque M
FAU - Gaydos, Christine
AU  - Gaydos C
FAU - Zask, Arie
AU  - Zask A
FAU - Chaudhary, Inder
AU  - Chaudhary I
FAU - Wang, Jianyao
AU  - Wang J
FAU - Di, Li
AU  - Di L
FAU - Young, Mairead
AU  - Young M
FAU - Ruppen, Mark
AU  - Ruppen M
FAU - Mansour, Tarek S
AU  - Mansour TS
FAU - Gibbons, James J
AU  - Gibbons JJ
FAU - Yu, Ker
AU  - Yu K
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Androstadienes)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/chemical synthesis/chemistry/*pharmacology
MH  - Animals
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Drug Design
MH  - Drug Stability
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Kidney Neoplasms/*drug therapy
MH  - Mice
MH  - Mice, Nude
MH  - Molecular Conformation
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Rats
MH  - Sirolimus/chemical synthesis/chemistry/*pharmacology
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Cells, Cultured
MH  - Wortmannin
MH  - Xenograft Model Antitumor Assays
EDAT- 2009/11/26 06:00
MHDA- 2010/02/03 06:00
CRDT- 2009/11/26 06:00
PHST- 2009/11/26 06:00 [entrez]
PHST- 2009/11/26 06:00 [pubmed]
PHST- 2010/02/03 06:00 [medline]
AID - 10.1021/jm901427g [doi]
PST - ppublish
SO  - J Med Chem. 2010 Jan 14;53(1):452-9. doi: 10.1021/jm901427g.