Recent Advances in the Development of PI3K/ mTOR-Based Anticancer Agents: A Mini Review

Cancer refers to the group of diseases characterized by uncontrolled growth of abnormal cells. It spreads throughout the body which makes this disease one of the huge global threats to mankind. Intensive research over the years has established deregulation of mammalian target of rapamycin pathway in cancer. This has led to the development of mammalian target of rapamycin inhibitors. Several inhibitors of the mammalian target of rapamycin are under preclinical and early clinical trials. Researchers have investigated a series of furoquinoline, phenyl sulphonylureas, 4-acrylamido-quinoline, pyrazolochalcones, imidazole [4,5-b] pyridine, thienopyrimidine, aminopyrimidin scaffolds in the last three years. This review provides comprehensive information and critical discussions on designing of novel selective inhibitors of mammalian target of rapamycin with superior activity in the treatment of cancer.


INTRODUCTION
Cancer is known as a group of diseases officially accountable for uncontrolled growth and spread of atypical cells. Many scientists have designed and synthesized compounds which act on breast cancer. 1 Breast cancer is one of the most frequent malignancies in women as around one in eight women will develop breast cancer in their lifetime. In the United States, this comes close to more than 200,000 new cases of invasive breast cancer each year, which will result in approximately forty thousand deaths. 2 In age-adjusted terms, this represents a combined male and female incidence of about a quarter of that recorded in Western Europe. According to the National Cancer Registry Programme of the India Council of Medical Research, more than 1300 Indians die every day due to cancer. 3 One of every two women newly diagnosed with carcinoma dies of cervical cancer every eight minutes in the Asian nation. 4,5 Consequently, there is an exigent need to explore some newer classes of therapeutics with selective action against cancer cells. The edict of cell proliferation and apoptotic pathways related to cell death is known as an important tactic to understand nearly these cells. 6,7 The phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) plays an important role in cell proliferation, advance, and angiogenesis. 8 mTOR is a critical signalling protein as it obliges as a cause of many pathways related to cell progress and means. This major pathway is deregulated: it can cause uninhibited activation of cancer cell progress and proliferation. This commonly results in malignancies that affect the kidney, breast and the neuroendocrine system. Deregulation of mTOR signalling is implicated in the development of several human diseases, including cancer, type 2 diabetes and obesity, highlighting the crucial role that mTOR plays in the maintenance of cellular homeostasis. 9 mTORC1 and mTORC2 are presented in regulated route. mTORC1 senses mutagenic signals and nutrient readiness in cells, and stimulates protein synthesis, particularly at the initiation step of the mRNA form. 12,13 Data in solid tumours demonstrated that the mTOR signal is dysregulated in almost 30% of cancers and is one of the most frequently affected cascades in human cancers. 14 [4,5-c]quinolin-2(3H)-one). Bendell JC et al. has reported pharmacokinetics demonstrating dose-dependent exposure with 90% target inhibition at doses of 150 mg. Drug-drug interaction analysis established LY3023414 to be a weak inhibitor of CYP3A4. 15 LY3023414 potently and by selection obstructs category I PI3K isoforms, DNA-PK, and mTORC1/2 with IC50 of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and a hundred sixty-five nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. LY3023414 vigorously inhibits mTORC1/2 at low nanomolar concentrations. 16 Lan Zheng et al. and co-researchers have investigated autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo (Fig. 2). 17

PI3K/AKT/mTOR (PAM) pathway
Activation of the phosphoinositide three enzymes (PI3K) /Akt/mammalian target of rapamycin (mTOR) pathway is common in carcinoma. There is diagnostic evidence to support inhibition of the pathway, and phase I to III clinical trials involving inhibitors of the pathway have been and are being conducted in solid tumours and breast cancer. 5 mTOR is the catalytic subunit of two functionally and structurally distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and 2 (mTORC2) that are defined by their necessary components Raptor (regulatory-associated protein of mTOR) and rapamycin-insensitive companion of mTOR (Rictor), respectively. 10 mTORC1 is a central regulator of protein blend, which is the most energy-unbearable infringement in the cell. 11 It is thus not unexpected that mRNA translation symbolizes a tightly
Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794. 19 García-Martínez JM

AZD2014
It is a small-molecule adenosine triphosphate competitive staple of mTOR that incumbents both mTORC1 and mTORC2 complexes and includes a finer repressive operate in contradiction of mTORC1 than the clinically approved rapalogs. Herein, AZD2014 has broad antiproliferative things diagonally numerous cell lines, including ERþ breast models with attained conflict to hormonal remedy and cell lines with acquired resistance to rapalogs. It is chemically 3-(2,4-bis((S)-3-methylmorpholino) pyrido[2,3-d] pyrimidin-7-yl)-N-methylbenzamide act on the intonation of both mTORC1 and mTORC2 substrates, locked with its mechanism of action. 21 Included has broad antiproliferative effects across multiple cell lines, including ER(+) breast models with acquired resistance to hormonal therapy and cell lines with acquired resistance to rapalogs. The ability to dose AZD2014 intermittently, together with its ability to block signalling from both mTORC1 and mTORC2 complexes, makes this compound a superlative candidate for combining with endocrine therapies in the clinic. AZD2014 is currently in phase II clinical trials (Fig. 4)

TAK-228
It is a pyrazolopyrimidin derivative exactly (3-(2-aminobenzo[d]oxazol-5-yl)-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine). Researchers have developed TAK-228 on the PI3K/AKT/mTOR pathway in preclinical studies and the frequency of pathway alterations in chronic tumours, which is a rational therapy for bladder sarcoma. This clinical investigation was done by the scientists proved how deviations in the PI3K/AKT/mTOR pathway connect with treatment. In preclinical bladder cell line mock-ups and xenografts done in our lab, the synergistic effect has been seen with the combination with paclitaxel. It is an investigational oral dual TORC1/2 inhibitor: A phase I dose-escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia (Fig. 6). 23

Furoquinoline based analogues
Manoj V. Loharet et al. 24 has premeditated a sequence of furoquinoline centred inhibitors of multiple bulls in the PI3K/Akt-mTOR pathway. Most of the complexes were originated to show clear-sightedness toward PI3K/Akt-mTOR and were found to be moderately heady. 4-(4-nitrophenylthio)-7-methoxyfuro[2,3-b]quinoline turns out to be the most active multi-targeted PI3K 48 μM and motor 49 μM inhibitor of this furoquinoline sequences. The PI3K/ mTOR inhibitory potency of it was further inveterate by Western blot analysis using the H-460 cell line for phosphorylation of Akt (PI3K) and 4E-BP1 (mTOR) at concentrations of 3 and 10 μM (Fig. 7).   display discernment toward PI3K/mTOR dual inhibitors. In particular, the cellular activity of the potent compounds 19a and 23b against MCF-7 cell was equal to the positive control soraffenib, through the IC50 value of 2.88±0.58 and 6.55±0.81, respectively. Structure-activity relationships (SARs) specified that the introduction of the methoxyl scaffold in 4-anilinoquinoline scaffold was new auspicious than the introduction of halogen to the cellular stir. 25  26 Miao Z et al. studied novel morpholine substituted thienopyrimidines as potential Class I PI3K/mTOR dual inhibitors. Dysfunctional signalling of the PI3K/AKT/mTOR pathway in cancer and its grave role in cell growth and survival has made it abundantly anticipated mark for cancer

Phenylsulfonylurea derivatives
Bingbing Zhao and co-workers have studied a chain of novel phenylsulfonylurea derivatives as PI3K/mTOR dual actions. The pharmacological results concentrated that most of the compounds showed a cytotoxicity sign alongside the cancer cell lines. Most of the compounds were found to therapeutics. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase activity, which had an approximately 8-fold improvement in motor shyness relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic variety of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. Besides, 14o demonstrated momentous usefulness in SKOV-3 and U87MG tumor xenograft models without causing weighty weight loss and toxicity. 27 Scaffolds of thienopyrimidine derivatives are presented in Fig. 9.

CONCLUSIONS AND FUTURE PERSPECTIVES
Herein, researchers have reported the design, synthesis, evaluation, and molecular docking of a sequence of different series of heterocycles as mTOR inhibitors with for the treatment of innumerable cancers. Most of the composites were originated to exhibit inhibitory potencies in the micromolar to sub-micromolar kind. The series of compounds was found to be selectively active in contradiction of PI3K/Akt/mTOR isoform. Last 3 years have perceived an exhaustive exploration of mTOR/PI3K inhibitory contours of various chemical scaffolds in early stages of improvement. Variability's PI3K/Akt/mTOR inhibitors are under clinical trials. Researchers have also investigated a novel series of furoquinoline, phenylsulphonylureas, 4-acry-lamido-quinoline, pyrazolochalcones, imidazole [4,5-b] pyridine, thienopyrimidine, aminopyrimidin scaffolds were designed and developed. As per Fig. 11 supreme of the compounds contain morpholine group is common. Based on our critical research, we observed that there still exist several shortcomings concerning advanced computational and experimental pharmacological studies to achieve prolific results. More significantly, the medicinal chemists and readers will gain evidence of various newly established PI3K/Akt/mTOR scaffolds and their development possibilities. The comprehensive evidence and critical negotiations provided herein will hopefully rush concepts for designing novel selective mTOR inhibitors with superior activity frameworks and inflict more caution in the verdict making process in the anticancer discovery.