Deforolimus (AP23573) a novel mTOR inhibitor in clinical development.
mTOR was determined to be a promising anticancer target and several drug inhibitors of mTOR are currently in clinical development. Rapamycin (RAP) was the first mTOR inhibitor discovered. However, RAP has poor aqueous solubility and chemical stability and therefore its utilization at doses susceptible to produce an effect as an anticancer agent is limited. This represented the main rationale for developing new RAP analogs. The RAP analogs currently in clinical development as anticancer agents include temsirolimus (CCI-779), everolimus (RAD-001), and deforolimus (AP23573). These agents have demonstrated antiproliferative activity against a diverse range of malignancies in preclinical studies, and clinical evaluations have been very encouraging thus far. Deforolimus (AP23573), a non-RAP prodrug, has been tested in Phase I and II clinical trials and shows promising results in several tumor types including sarcoma. A Phase III study in patients with sarcoma is currently ongoing. The preclinical and clinical studies with deforolimus will be presented.
Mita
Monica
M
Institute for Drug Development, Cancer Therapy and Research Center, UT Health Science Center, San Antonio, USA. mitam@uthscsa.edu
Sankhala
Kamalesh
K
Abdel-Karim
Issam
I
Mita
Alain
A
Giles
Francis
F
D000818:Animals; D002986:Clinical Trials as Topic; D000068338:Everolimus; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus