Catalytic mammalian target of rapamycin inhibitors as antineoplastic agents.
The mammalian target of rapamycin (mTOR) pathway is a major therapeutic target in the treatment of hematological malignancies, as it controls cellular events of high importance for regulation of mRNA translation and protein production. Rapalogs, or first-generation mTOR inhibitors, have produced only modest clinical benefits so far. Limitations to rapalogs likely result from the partial inhibition of mTORC1 substrates and lack of effects on mTORC2. Efforts toward the development of agents with more potent and complete inhibitory effects on the mTOR pathway have resulted in the development of catalytic mTOR inhibitors. Key preclinical and early clinical investigations of several catalytic mTOR inhibitors and potential resistance mechanisms to their activities are summarized here.
b Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
Nisha A
NA
Mohindra
a Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.|b Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.|c Division of Hematology-Oncology, Department of Medicine , Jesse Brown Veterans Affairs Medical Center , Chicago , IL , USA.
Leonidas C
LC
Platanias
D001549:Benzamides; D001583:Benzoxazoles / Q000627:therapeutic use; D055162:Biocatalysis / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines / Q000627:therapeutic use; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use; D000225:Adenine / Q000031:analogs & derivatives
D001549:Benzamides; D001583:Benzoxazoles; D007093:Imidazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C568605:OSI 027; C585537:vistusertib; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine
leukemia; lymphoma; mTOR