azd2014 and Hematologic-Neoplasms

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.

Topics: Benzamides; Benzoxazoles; Biocatalysis; Hematologic Neoplasms; Humans; Imidazoles; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Morpholines; Multiprotein Complexes; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Triazines