INTRODUCTION:

A quinoxaline is a heterocyclic organic compound with the chemical formula C₈H₆N₂. It is characterized by a benzene ring attached to a pyrazine ring, and its unique chemical properties make it widely used as a building block in synthesizing other compounds^1,2. Quinoxalines and their derivatives possess many biological activities, like antifungal, antibacterial, antiviral, and anti-inflammatory effects. It is also used as a fluorescent dye and as an organic semiconductor. In current years, quinoxaline derivatives have attracted attention as potential agents for treating many diseases like cancer, Alzheimer's, and diabetes. In particular, some quinoxaline derivatives have shown promise as dual inhibitors of the mTOR/PI3K signalling pathway, which is often dysregulated in cancer as well as other diseases. In this Article, we Review the Different Drugs that are developed from Quinoxaline as a base structure and have anti-cancer properties.

The review work was done by thoroughly searching various research articles from various online journals like PubMed, Google Scholar, Science Direct, etc. We have also documented drugs in clinical trials that have been scientifically confirmed to have good anti-cancerproperties.

PI3K:

It is a lipid kinase class that regulates signalling and intracellular vesicle trafficking through phosphorylation of intracellular inositol lipids. PI3Ks are categorized into 3 types as per their properties and the substrate mechanisms they use. Class I PI3Ks synthesize inositol-3-phospholipids that directly activate signalling pathways. Class I PI3Ks are divided into sub-classes IA and IB depending on the control mechanism. The PI3Ks of Class IA are heterodimers that contain p85 as the regulatory sub-unit and p110 as the catalytic sub-unit. Class IA catalytic isoforms p110δ, p110β, and p110α are encoded by genes PIK3CD, PIK3CB, and PIK3CA, correspondingly. Class I PI3Ks are heterodimers containing the catalytic subunit of p110γ and the regulatory subunit of p87 or p101. Class IB isoforms p87, p101, or p110γ are encoded by genes PIK3R6, PIK3R5, or PIK3CG. Class I PI3Ks, which are involved in translation, proliferation of cells, cytoskeletal motility, glucose metabolism, survival of cells, and transformation, are typically active in malignant tumours^3,4. Class II PI3Ks are responsible for controlling various cellular activities, like proliferation, cell migration, the function of the pilus, cell survival, glucose metabolism, and angiogenesis. Class II catalytic isoforms PI3KC2γ, PI3KC2β, and PI3KC2α are encoded by genes PIK3C2G, PIK3C2B, and PIK3C2A, correspondingly. Endosomal trafficking, Autophagy, and phagocytosis depend on class III PI3Ks. Class III PI3Ks are heterodimers made up of the catalytic subunit VPS34 encoded by PIK3C3 and the regulatory and accessory component VPS15 encoded by PIK3R4. Several PI3K-specific inhibitors are currently under development. PI3K inhibitors may be divided into 3 groups based on their pharmacokinetic properties and ability to interact with the ATP binding site: dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-selective PI3K inhibitors.

mTOR inhibitors:

The mTOR family of kinases is generally classified into 3 roles. Sections (i) mTOR1, (ii) mTOR2, (iii) mTOR3. mTOR1 and mTOR2 are associated with cancer. mTORC1 functions as a downstream effector of multiple oncogenic signalling pathways, which includes MAPK and AKT/PI3K signalling. And mTOR signalling is hyperactivated in many types of tumors^5,6. This makes mTOR a target for cancer therapy. mTOR inhibitors are a class of drugs that work by selectively inhibiting the activity of mTOR. In general, mTOR inhibitors fall into 2 classes. Rapamycin and its analogues (rapalogs), and ATP-competitive mTOR kinase inhibitors. The first can block mTORC1 and the second can block mTORC1/2. Dual mTOR/PI3K inhibitors disrupted the ATP binding gap between mTOR and PI3K, reduced the kinase activity of the two enzymes, and affected signalling activity more than mTOR kinase inhibitors alone. Dual mTOR/PI3K inhibitors have exhibited potential in previous studies.^7,8,9 If dual mTOR/PI3K inhibitors are more efficient in comparison with mTOR inhibitors, further research is required. Dual mTOR/PI3K inhibitors like ductalisib (BEZ235), Patricia (GDC-0980), gedatricib (PF-05212384), vimiralisib (PQR309), boktarib (SAR2456409) and paxalisib (GDC-0084) are effective and their structures have given in figure 1.

Figure 1: represents the structure of some Dual mTOR/PI3K inhibitors

Quinoxaline derivatives as dual inhibitors of PI3K and mTOR:

Various quinoxaline derivatives have been known as potent dual inhibitors of PI3K and mTOR. One such example is PX-866, which has been shown in previous studies to be effective against several types of cancer. PX866 inhibits mTOR and PI3K kinase by binding to the ATP binding site. Another quinoxaline derivative, PKI-587, also exhibited potent inhibitory activity against her mTOR and PI3K in previous studies. PKI-587 is being studied in multiple clinical trials in treating cancers, such as non-small cell lung cancer as well as breast cancer.

Mechanism of action:

The mTOR/PI3K signalling pathway is involved in essential processes that are crucial for the growth, development, as well as survival of cells. PI3K catalyses the conversion of PIP2 (“phosphatidylinositol 4,5-bisphosphate”) to PIP3 (“phosphatidylinositol 3,4,5-trisphosphate”) and activates downstream effectors like Akt and mTOR.^11,12Akt controls many cellular processes like survival, growth, as well as the metabolism of cells while mTOR controls cell growth and protein synthesis. B.-quinoxaline derivatives^13,14, dual PI3K, and mTOR inhibitors inhibit cancer cell development and cell proliferation by blocking the signalling of these two key factors. The mTOR/PI3K signalling pathway is a protein network which plays a very crucial role in regulating many cellular processes like growth, proliferation, differentiation, and survival of the cell. It is activated by growth factors, cytokines, and other extracellular signals^15, that bind to transmembrane receptors like G protein-coupled receptors and receptor tyrosine kinases. Growth factors and cytokines are two examples of these extracellular signals. The production of PIP3 and the recruitment of downstream effector proteins, like the threonine/serine kinase Akt, are both results of the activation of the mTOR/PI3K pathway^16,17 (also known as protein kinase B). Activation. mTOR, a key regulator in cell growth and metabolism, is turned on as a result of Akt's activation of it. The mTOR/PI3K signalling pathway is frequently aberrant in cancer, which has negative effects on both the survival and proliferation of the cancer cells. There is evidence that mutations in genes that code for components of this signalling pathway, like AKT, PIK3CA, and PTEN, are linked to the growth of various cancers.¹⁸Targeted therapies for this signalling pathway therefore represent a promising cancer therapy. The mTOR/PI3K pathway is being targeted by a huge number of medications that are now being tested in clinical trials. These drugs include dual mTOR/PI3K inhibitors, PI3K inhibitors, and mTOR” inhibitors.¹⁹These medications have demonstrated potential in both preclinical as well as early clinical research, and several of them are already authorized for the treatment of many cancers. However, its application in clinical settings is constrained by several reasons, including toxicity and drug resistance. The ATP binding gap between PI3K and mTOR is disrupted by PI3K/mTOR inhibitors, as illustrated in Figure 2. These inhibitors also diminish the kinase activity of both enzymes and have a greater impact on signalling activity than mTOR kinase inhibitors alone.²⁰ In prior research, dual PI3K/mTOR inhibitors have demonstrated promising results. It is essential to conduct additional research to ascertain whether or if dual mTOR/PI3K inhibitors are superior to his mTOR inhibitors.

Figure 2: illustration of PI3K/mTOR Pathway

Preclinical studies:

Quinoxaline derivatives have shown promising results in preclinical studies.^21,22 For example, PX-866 was displayed to inhibit many cancer cell growth, including those resistant to other Her PI3K inhibitors. PX-866 has also been shown to be effective against cancer cells that are thought to cause tumour recurrence and metastasis.

Similarly, PKI-587 was displayed to inhibit the development of many cancers, like breast, lung, and pancreatic cancers. PKI-587 has also been shown to improve the anti-inflammatory impacts of various chemotherapeutic agents like docetaxel and gemcitabine.

Clinical trials:

In clinical studies, numerous quinoxaline derivatives of varying sorts are being investigated for their potential to cure various cancers. For pancreatic cancer, non-small cell lung cancer, and breast cancer treatment²³, PKI-587 is now tested in clinical studies for Phase I and Phase II. Patients having advanced tumours who took part in a Phase I trial of PKI-587 exhibited that the medicine was well tolerated, and there were no adverse effects noted.

In non-small cell lung cancer as well as breast cancer groups, PKI-587 demonstrated anti-tumour efficacy.

PX-866 is a quinoxaline derivative and a potent PI3K inhibitor. Specifically, it inhibits the alpha is oform of PI3K and has been shown in previous studies to be effective against various types of cancer^24,25. PX-866 can inhibit the activity of PI3K by binding to the ATP-binding site of the kinase, which in turn prevents the pathway from functioning.

PX-866 has a substantial inhibitory effect against PI3K, and it also inhibits the mTOR, which is another significant signalling pathway that affects cell growth and survival. PX-866 dually inhibits her PI3K and mTOR, making it an excellent candidate for cancer therapy. This is because dysregulation of this signalling pathway is common in cancer²⁶. Preliminary studies have shown that PX-866 is effective against many cancer types including lung, breast, pancreatic, and melanoma^27,28 It has also been shown to be effective against cancer cells that are thought to cause tumour recurrence and metastasis. In his phase I trial with PX-866, the medicine was well tolerated, and no severe toxicities were found in the patients who had advanced tumours.

PX-866:

PX-866 is now tested in many clinical trials for use in combating a wide range of cancers. In this phase I trial with PX-866, the medicine was well tolerated, and no severe toxicities were found in the patients who had advanced tumours. However, treatment efficacy is limited and some patients respond only partially to the drug. His subsequent phase II trials of PX-866 in patients having advanced or recurrent breast cancer or breast cancer did not show clinically relevant benefits and PX-866 was not developed as a monotherapy.

Despite its disappointments in clinical trials, PX-866 remains important in understanding her PI3K/mTOR signalling pathway and its role in cancer.

Its strong inhibitory activity against PI3K and mTOR makes it a vital tool for researchers studying these signalling pathways and their dysfunction in cancer.

PKI-587:

PKI-587 is a tiny chemical that inhibits the PI3K and rapamycin (mTOR) pathways in mammalian targets. In particular, it inhibits all four isoforms of PI3K and mTOR kinase, making it a dual inhibitor of key signals. Cancer is characterized by a widespread dysregulation of the mTOR/PI3K signalling system, which has been linked to tumour growth, survival, and metastasis.

Therefore, PKI-587 has emerged as a potential drug candidate for breast cancer treatment. Preclinical studies have shown that PKI-587 is effective against multiple cancers including breast, prostate, glioblastoma, and ovarian cancer^29,30. It has also been shown to be effective against cancer cells that are thought to cause tumour recurrence and metastasis. PKI-587 works by preventing cancer cells from dividing and killing themselves through a process known as apoptosis.

PKI-587 is being assessed in multiple clinical trials for treating various cancers.

Patients with advanced tumours who took part in a Phase I trial of PKI-587 exhibited that the medicine was well tolerated, and there were no adverse effects noted. Clinical activity was observed in a small number of patients, some of whom partially responded to the drug. After this, patients with advanced ovarian cancer and patients having metastatic triple-negative breast cancer took part in Phase II clinical studies of PKI-587. Showed a complete response to the drug in some patients and a positive effect on treatment. Dual inhibition of mTOR and PI3K by this pathway is often associated with cancer, making PKI-587 a candidate for cancer therapy.

Furthermore, its ability to attack cancer cells suggests that it may be effective against tumour growth and metastasis, which are major problems in cancer therapy³¹. However, to assess the efficiency as well as the safety of PKI-587 in treating various cancers, additional clinical tests will need to be conducted.

VS-5584:

A mammalian target of both the PI3K and the mTOR pathways can be inhibited by the small chemical VS-5584.In particular, it inhibits PI3K/mTOR complexes 1 and 2³² These signalling pathways play a prime role in controlling cell growth, proliferation, and lifespan. Cancer is characterized by a widespread dysregulation of the mTOR/PI3K signalling system, which has been linked to tumour growth, survival, and metastasis. Consequently, VS-5584 has developed as a potentially useful therapeutic candidate for treating cancer.

Preclinical studies have exhibited that VS-5584 is effective against various kinds of cancer, including breast and pancreatic cancer. ¹⁸, lung cancer and melanoma. Table 1 summarizes the clinical trial information of some drugs.

Table 1: Certainly! Here’s a table summarising the clinical trial information for the mentioned drugs:

Drug	Mechanism	Targets	IC50 (nM)	Indications	Clinical Trial
Dactolisib	Dual ATP-competitive PI3K and mTOR inhibitor	p110α/γ/δ/β and mTOR (p70S6K)	4 (p110α), 5 (p110γ), 7 (p110δ), 75 (p110β), 6 (mTOR)	Evaluated in solid tumours	A phase II study compared BEZ235 with everolimus in patients with advancedpancreatic neuroendocrine tumours (pNET) who were naïve to mTOR inhibitor therapy.
Apitolisib	Potent class I PI3K inhibitor for PI3Kα/β/δ/γ	PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ	5 (PI3Kα), 27 (PI3Kβ), 7 (PI3Kδ), 14 (PI3Kγ)	Evaluated in various solid tumours	Phase I study in patients with advanced solid tumours.
Alpelisib	PI3Kα-specific inhibitor	N/A	N/A	Evaluated in breast cancer and other malignancies	Investigated in various trials, including the SOLAR-1 trial for advanced breast cancer.
Boktarib	Unfortunately, detailed clinical trial info N/A	N/A	N/A	N/A	Unfortunately, detailed clinical trial information is not readily available.
Paxalisib	PI3K inhibitor	N/A	N/A	Evaluated in glioblastoma	Investigated in clinical trials for glioblastoma and other malignancies.
Idelalisib	PI3Kδ-specific inhibitor	N/A	N/A	Used in chronic lymphocytic leukaemia (CLL) and follicular lymphoma	Extensively studied in CLL and other hematologic malignancies.
Everolimus	mTOR inhibitor	N/A	N/A	Used in various cancers, including renal cell carcinoma, pancreatic neuroendocrine tumours, and breast cancer	It is widely investigated in clinical trials across different cancer types.

In patients having advanced cancers who were participating in a Phase I trial of VS-5584, the medicine was positively received and there was no evidence of harm. A limited number of individuals have shown clinical activity, some of whom only partly reacted to the medication. Positive clinical efficacy was observed in a later phase II trial of VS-5584 in patients having non-small cell lung cancer as well as metastatic or recurrent neck and head cancer. Some of the participants in the trial displayed some type of reaction to the treatment. Complex 1 and 2 of the mTOR/PI3K pathway are inhibited.^33,34

This pathway is often associated with cancer, making VS-5584 a candidate for cancer therapy. Furthermore, its ability to target cancer cells suggests that it may be effective against tumour recurrence and metastasis, which are challenges in cancer therapy.

However, to examine the efficacy and safety of VS-5584 in its various modified forms, additional clinical tests will need to be conducted. The PI3K/PKB/mTOR signalling pathway is a vital system that is involved in various biological functions, like the growth of cells, proliferation of cells, survival of cells, and metabolism^35,36. The abnormal dysregulation of this pathway has been linked to the beginning as well as the progression of various cancers.

Activation of PI3K/PKB/mTOR signalling pathway:

In normal cells, the PI3K signalling pathway is activated by proliferation, Because of this activation of the AKT/PKB signalling pathway, and target. mTOR is activated. The promotion of growth, proliferation, and survival of cells can be achieved by activation of the PI3K/PKB/mTOR signalling pathway.

However, in cancer cells, this signalling pathway is often disrupted, leading to the growth and multiplication of cells that are out of control, resistance to the process of apoptosis, and increased angiogenesis.

Because of this, targeting the PI3K/PKB/mTOR signalling pathway as part of cancer treatment has emerged as a promising future strategy^37,38.

Several medicines that target individual components of this pathway have been created, and some of them are now being tested in human patients. These medications include things like PI3K inhibitors,^39,40mTOR inhibitors, and AKT inhibitors, to name a few examples. Although some of these agents are efficient in clinical trials, the safety, as well as efficacy of these agents, are still under investigation and many studies were required to understand well the role of the PI3K/PKB/mTOR signalling pathway in cancer and also enable the development of better treatments. Target-targeted selective and non-selective small molecules PI3K/PKB/mTOR signalling pathway.⁴¹

Small molecules that target the PI3K/PKB/mTOR pathway could be” selective or non-selective.

Selective small molecules are designed to inhibit specific proteins within signalling pathways, whereas non-selective small molecules target many proteins within signalling pathways. Selective inhibitors may have advantages over non-selective inhibitors by targeting proteins involved in cancer initiation and progression, which can reduce unwanted side effects and increase efficacy.

Below are examples of selective and non-selective small molecules targeting the PI3K/PKB/mTOR pathway^,42.

Selective inhibitor:

Idelalisib –chronic lymphocytic leukaemia (CLL) and follicular lymphoma treatment that uses a PI3Kδ inhibitor.

Alpelisib- A breast cancer treatment that is either hormone receptor-positive, HER2-negative, or a PI3Ka inhibitor.

Everolimus – mTOR inhibitor is a type of medication that is indicated for treating renal cell carcinoma, subependymal giant cell astrocytoma, and pancreatic neuroendocrine tumours.

Non-selective inhibitor:

Rapamycin - an mTOR inhibitor utilized for treating renal cell carcinoma and being studied for other types of cancer.

DISCUSSION:

In this review article, we discuss the various drugs Clinical studies for treating various cancers are presently underway, and one of the drugs being tested is called BEZ235. BEZ235 is a dual inhibitor of PI3K and mTOR. In clinical studies, the dual mTOR/PI3K inhibitor known as GDC-0980 is being examined to determine whether or not it can effectively treat a variety of cancers. These small molecules displayed potential findings in clinical and clinical research, and many are currently utilized or evaluated in clinical trials to treat cancer. The study also revealed that targeted cancer therapy based on agents that block one or more steps of the PI3K/PKB/mTOR signalling pathway is a cancer treatment strategy.

CONCLUSION:

The PI3K/PKB/mTOR signalling pathway is an essential component in the process of determining how long a cell can live, as well as how it grows and develops. Because problems with this particular signalling system are seen in a wide variety of cancers, cancer treatment should focus on addressing these issues. Quinoxaline derivatives as PI3K/mTOR inhibitors were created that can block one or more steps in this signalling pathway, and many of them have shown promise in clinical and clinical studies. Cancer-targeted therapies based on agents that block the PI3K/PKB/mTOR signalling pathway are more effective than chemotherapy. These agents can selectively target cancer cells that rely on this pathway to survive and proliferate in the absence of normal cells. Additionally, it has the potential to lessen chemotherapy’s negative effects and boost the overall quality of life of cancer patients.

Overall, cancer therapeutic strategies based on agents that block the PI3K/PKB/mTOR pathway have displayed promise in cancer treatment and represent promising cancer therapies.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank AKS University for their kind support.

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Received on 05.10.2023 Modified on 08.01.2024

Research J. Pharm. and Tech 2024; 17(8):4068-4074.

DOI: 10.52711/0974-360X.2024.00631