Contemporary mTOR inhibitor scaffolds to diseases breakdown: A patent review (2015–2021)
Graphical abstract
Introduction
Rapamycin is a natural product, first isolated in 1975 as an antibiotic from a soil bacteria Streptomyces hygroscopicus found on Easter Islands. Its original name is derived from “Rapa Nui”, the native name of the island [1]. Rapamycin was initially associated with antifungal activity, however in 1977 an immunosuppressant effect and in 1983 an antitumor effect of rapamycin was discovered [2,3]. In 1991, elucidating of rapamycin's molecular mechanism of action resulted in discovery of target of rapamycin 1 (TOR1) protein in yeast, following by discovery of target of rapamycin 2 (TOR2) in 1993 [4,5]. Mammalian TOR, later named as mechanistic TOR (mTOR) was discovered in 1994. It has been found that mTOR, a major cellular crossroad in mTOR signaling pathway, plays an important role in different fundamental cell processes, such as protein synthesis, cell motility, cell proliferation and survival, gene transcription, and autophagy. Further studies revealed a linkage between dysregulated mTOR signaling pathway and various diseases including cancer, insulin resistance, arthritis, osteoporosis, neurological and neuropsychiatric diseases. Moreover, the signaling pathway is also associated with aging. Inhibition of overactivated mTOR signaling pathway provides beneficial health effects in different pathological conditions [6]. Nowadays, structurally variable mTOR inhibitors have reached clinical trials, whereas selected are already approved and applied in clinical practice [7]. These and upcoming mTOR inhibitors will extend our knowledge about role of mTOR in cell as well as human diseases. Deeper understanding of mTOR functions and therapeutic potential resulted from rapamycin-mediated mTOR inhibition provided a wide group of rapamycin analogs, termed as rapalogs. Rapalogs are the first generation mTOR inhibitors that increased an interest of global research community in mTOR inhibitory potential. This interest yielded to discovery of second and third generation of mTOR inhibitors [8]. Herein we summarize a potential mTOR inhibitors reported in patents from 2015 to 2021.
Section snippets
mTOR
The mTOR is a highly conserved serine/threonine protein kinase which catalyzes phosphate transfer to hydroxyl group of serine or threonine. The kinase is an evolutionarily conserved, 289 kDa large protein consisting of 2549 amino acids that belongs to phosphoinositide 3-kinase (PI3K)-related protein kinase (PIKK) family. The mTOR interacts with several proteins to form two different mTOR complexes (mTORCs) regulating essential processes in cell. By this reason, mTOR is considered as a key
mTOR inhibitors
Considering that overactivated mTOR is associated with pathogenesis and disorders, inhibitors of mTOR activity are considered as potential therapeutic targets. Inhibition of mTOR activity may be beneficial in treatment of cancer, neurodegenerative diseases, cardiovascular disease, diabetes, obesity as well as in delaying of aging. Nowadays, mTOR inhibitors represent a group of various compounds with diverse structural varieties. The inhibitors are usually classified into three generations
mTOR inhibitors in clinical use
Despite a broad effort of the scientific community worldwide, only few mTOR inhibitors are currently applied in clinical use. In addition, all of the approved mTOR inhibitors belong to the first generation of mTOR inhibitors. These inhibitors are used for treatment of cancer or to prevent transplant rejection. Rapamycin was first mTOR inhibitor approved by the United States Food and Drug Administration (FDA) in 1999, under the brand name Rapamune®, as an immunosuppressive drug to prevent
Conclusion
The mTOR kinase plays a key role in PI3K/AKT/mTOR signaling pathway regulating different cellular processes. Hyperactivated mTOR function is associated with several pathological conditions in humans. An ambition to regulate activity of the kinase is represented by various research groups developing mTOR inhibitors. A plenty of mTOR inhibitors has been prepared over the last decades. Nowadays, the inhibitors are classified into three generations having different mode of action. In addition, the
Expert opinion
There are no doubts that mTOR plays a key role in cell maintenance. The mTOR signaling pathway is involved in essential functions regulating cell growth, proliferation, survival and autophagy. However, dysregulation in mTOR signaling is associated with various complications known as mTOR-related diseases. Overactivated mTOR activity was observed in different types of cancer. Moreover, mTOR signaling is closely related to neurodegenerative disease such as Alzheimer's disease, Parkinson's
Funding
This review was supported by 20-22037S of the Czech Science Foundation.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kamil Kuca reports was provided by University of Hradec Kralove.
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2023, European Journal of Medicinal ChemistryCitation Excerpt :mTOR is a fundamental key protein within the cell and can be described as nodal for convergence and sorting of a wide range of information, modulating various cellular physiological processes. The mTOR-mediated pathway is generally deregulated in human cancers, thus representing an attractive target for the development of new therapeutic agents [18]. mTOR inhibitors so far identified can be divided into three generations: