Nelfinavir

Q1: What is the primary mechanism of action of Nelfinavir?

A1: this compound was initially developed as a specific inhibitor of human immunodeficiency virus (HIV) protease. [] It exerts its antiviral activity by binding to the active site of the HIV-1 protease, thereby preventing the cleavage of viral polyproteins and inhibiting viral maturation. []

Q2: How does this compound's activity extend to anti-cancer effects?

A2: Beyond its antiviral activity, this compound exhibits pleiotropic effects in various cancer cells. [, ] One key mechanism involves the induction of endoplasmic reticulum (ER) stress, leading to the unfolded protein response (UPR) and ultimately apoptosis (programmed cell death). [, , ] Additionally, this compound inhibits the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, a key regulator of cell growth and survival, further contributing to its anti-cancer properties. [, ]

Q3: this compound has been shown to affect lipid metabolism in cancer cells. Can you elaborate?

A3: this compound inhibits the activity of Site-2 protease (S2P), an enzyme involved in the regulated intramembrane proteolysis (RIP) of sterol regulatory element binding protein-1 (SREBP-1) and activating transcription factor 6 (ATF6). [] This inhibition disrupts lipid homeostasis, contributing to ER stress and promoting cell death.

Q4: Can you explain the role of this compound in modulating the unfolded protein response (UPR) and its impact on cancer cells?

A4: this compound activates the UPR in myeloma cells, leading to the upregulation of UPR-related proteins. [] This activation can overcome proteasome inhibitor resistance often observed in multiple myeloma. [] The exact mechanisms underlying this effect are complex but involve modulation of key UPR sensors and downstream effectors.

Q5: How does this compound impact the tumor microenvironment?

A5: this compound downregulates hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) expression, leading to decreased angiogenesis (formation of new blood vessels). [] This, in turn, increases tumor oxygenation, potentially enhancing the efficacy of radiotherapy. []

Q6: What is the role of oxidative stress in this compound's anticancer activity?

A6: this compound has been shown to increase reactive oxygen species (ROS) production in breast cancer cells, leading to disruption of the Akt/HSP90 complex and subsequent Akt degradation, ultimately contributing to cell death. [] This ROS-dependent mechanism appears to be selective for cancer cells, sparing normal breast cells. []

Q7: What is the molecular formula and weight of this compound?

A7: this compound mesylate, the salt form commonly used in formulations, has the molecular formula C32H45N3O4S • CH4O3S and a molecular weight of 663.87 g/mol.

Q8: Have any computational studies been performed on this compound?

A8: Yes, computational methods have been used to develop a pharmacophore model for this compound interaction with the multidrug resistance protein 4 (MRP4/ABCC4). [] This model revealed that this compound shares a binding site with chemotherapeutic agents like adefovir and methotrexate, highlighting its potential as both a substrate and inhibitor of this transporter. []

Q9: What is the typical route of administration and absorption profile of this compound?

A10: this compound is administered orally. [, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ] Food significantly affects its absorption, with a high-calorie meal required to achieve optimal plasma concentrations. []

Q10: How is this compound metabolized in the body?

A11: this compound undergoes extensive metabolism in the liver, primarily by cytochrome P450 (CYP) enzymes, mainly CYP3A4 and CYP2C19. [, ] The major metabolite, this compound hydroxy-t-butylamide (M8), exhibits potent antiviral activity. [, , ]

Q11: What factors can influence the pharmacokinetics of this compound?

A11: Various factors can influence this compound pharmacokinetics, including age, co-administered medications, and liver function. For instance:

• Age: Children, especially infants, exhibit different pharmacokinetic profiles compared to adults, generally requiring higher doses to achieve similar drug exposure. [, , ]
• Co-administered drugs: Co-administration with other protease inhibitors can lead to significant drug interactions, altering the plasma concentrations of both drugs. [, , ] Similarly, drugs that induce or inhibit CYP3A4 can impact this compound metabolism. []
• Liver disease: Liver disease, especially moderate to severe, can impair this compound metabolism, leading to lower M8 formation and requiring dose adjustments. []

Q12: How do this compound plasma concentrations relate to its efficacy in treating HIV?

A13: Studies suggest a correlation between this compound plasma concentrations and virological treatment success in HIV-infected individuals. Patients with low this compound levels are at an increased risk of virologic failure. [] This finding highlights the importance of therapeutic drug monitoring to optimize treatment outcomes.

Q13: What types of in vitro models have been used to study this compound?

A14: Various in vitro models, including cell lines derived from different cancer types (e.g., breast, lung, ovarian, multiple myeloma) have been used to investigate this compound's anti-cancer effects. [, , , , , , ] These studies have provided insights into its mechanisms of action, such as induction of apoptosis, ER stress, and inhibition of specific signaling pathways. [, , , , , ]

Q14: What in vivo models have been employed to evaluate this compound's anti-cancer potential?

A15: this compound's in vivo efficacy has been assessed in various animal models, including mouse xenograft models of different cancer types. [, , , ] These studies have demonstrated that this compound can inhibit tumor growth in vivo, often in conjunction with markers of ER stress, autophagy, and apoptosis. [, , , ]

Q15: Have any clinical trials been conducted with this compound in cancer patients?

A15: Yes, several clinical trials have explored this compound's potential as an anti-cancer agent in humans. For instance:

• Phase I trials: These trials have primarily focused on establishing the maximum tolerated dose (MTD) and safety profile of this compound in patients with advanced solid tumors. [] Results indicate that this compound is generally well-tolerated at doses higher than those used for HIV treatment. []
• Phase I/II trials: A trial combining this compound with bortezomib in patients with advanced hematologic malignancies demonstrated promising activity, particularly in bortezomib-refractory multiple myeloma. []

Q16: What are the primary HIV protease mutations associated with this compound resistance?

A17: The D30N mutation is the most common primary resistance mutation selected for by this compound. [, ] While it confers minimal cross-resistance to other protease inhibitors, the emergence of L90M, often accompanied by secondary mutations, can lead to broad cross-resistance within the protease inhibitor class. []

Q17: How does this compound resistance impact subsequent treatment options for HIV?

A18: Interestingly, despite the emergence of D30N, many patients experiencing virologic failure on a this compound-containing regimen can successfully switch to another protease inhibitor and achieve viral suppression. [, ] This observation suggests that the development of cross-resistance, while possible, is not inevitable.

Q18: Is there any evidence of cross-resistance between this compound and other anti-cancer agents?

A19: While this compound demonstrates synergism with some chemotherapeutic agents, like bortezomib, [, ] specific information regarding cross-resistance patterns with other anti-cancer drugs is limited within the provided research papers.