Discovery and development of mTOR inhibitors

mTOR inhibitors are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs (rapamycin and its analogs), which have shown tumor responses in clinical trials against various tumor types. The discovery of mTOR was made a few decades ago while investigating the mechanism of action of its inhibitor, rapamycin. Rapamycin was first discovered in 1975 in a soil sample from Easter Island of South Pacific, also known as Rapa Nui, from where its name is derived. Rapamycin is a macrolide, produced by the microorganism Streptomyces hygroscopicus and showed antifungal properties. Shortly after its discovery, immunosuppressive properties were detected, which later led to the establishment of rapamycin as an immunosuppressant. In the 1980s, rapamycin was also found to have anticancer activity although the exact mechanism of action remained unknown until many years later. In the 1990s there was a dramatic change in this field due to studies on the mechanism of action of rapamycin and the identification of the drug target. It was found that rapamycin inhibited cellular proliferation and cell cycle progression. Research on mTOR inhibition has been a growing branch in science and has promising results. In general, protein kinases are classified in two major categories based on their substrate specificity, protein tyrosine kinases and protein serine/threonine kinases. Dual-specificity kinases are subclass of the tyrosine kinases. mTOR is a kinase within the family of phosphatidylinositol-3 kinase-related kinases (PIKKs), which is a family of serine/threonine protein kinases, with a sequence similarity to the family of lipid kinases, PI3Ks. These kinases have different biological functions, but are all large proteins with common domain structure. PIKKs have four domains at the protein level, which distinguish them from other protein kinases. From the N-terminus to the C-terminus, these domains are named FRAP-ATM-TRAAP (FAT), the kinase domain (KD), the PIKK-regulatory domain (PRD), and the FAT-C-terminal (FATC). The FAT domain, consisting of four α-helices, is N-terminal to KD, but that part is referred to as the FKBP12-rapamycin-binding (FRB) domain, which binds the FKBP12-rapamycin complex. The FAT domain consists of repeats, referred to as HEAT (Huntingtin, Elongation factor 3, A subunit of protein phosphatase 2A and TOR1). Specific protein activators regulate the PIKK kinases but binding of them to the kinase complex causes a conformational change that increases substrate access to the kinase domain. Protein kinases have become popular drug targets. They have been targeted for the discovery and design of small molecule inhibitors and biologics as potential therapeutic agents. Small-molecule inhibitors of protein kinases generally prevent either phosphorylation of proteins substrates or autophosphorylation of the kinase itself. It appears that growth factors, amino acids, ATP, and oxygen levels regulate mTOR signaling. Several downstream pathways that regulate cell-cycle progression, translation, initiation, transcriptional stress responses, protein stability, and survival of cells are signaling through mTOR.