Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.

The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2, and more recently also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and non-protective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome resistance development. Significance Statement This manuscript is one in a series of papers that investigate the different roles of the autophagic machinery induced in response to versatile anti-neoplastic agents in various cancer models. This series designed in an attempt to build a conclusion whether autophagy targeting or modulation is an effective adjuvant strategy to increase the efficacy of chemotherapeutic agents. In this review, we shed the light on the relationship between the autophagic machinery and HER2 targeted therapies.

VERU-111, an Orally Available Tubulin Inhibitor, Suppresses Ovarian Tumor Growth and Metastasis.

Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, well-tolerated, and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and, ultimately, apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment for ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. Significance Statement VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo anti-tumor and anti-metastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.

Time-dependent proteomics and drug response in expanding cancer cells.

Cancer cell line is commonly used for discovery and development of anti-cancer drugs. It is generally considered that drug response remains constant for a certain cell line due to the identity of genetics thus protein patterns. Here, we demonstrated that cancer cells continued dividing even after reaching confluence, in that the proteomics was changed continuously and dramatically with strong relevance to cell division, cell adhesion and cell metabolism, indicating time-dependent intrinsically reprogramming of cells during expansion. Of note, the inhibition effect of most anti-cancer drugs was strikingly attenuated in culture cells along with cell expansion, with the strongest change at the third day when cells were still expanding. Profiling of an FDA-approved drug library revealed that attenuation of response with cell expansion is common for most drugs, an exception was TAK165 that was a selective inhibitor of mitochondrial respiratory chain complex I. Finally, we screened a panel of natural products and identified four pentacyclic triterpenes as selective inhibitors of cancer cells under prolonged growth. Taken together, our findings underscore that caution should be taken in evaluation of anti-cancer drugs using culture cells, and provide agents selectively targeting overgrowth cancer cells.

Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.

Druggable targets of protein tyrosine phosphatase Family, viz. PTP1B, SHP2, Cdc25, and LMW-PTP: Current scenario on medicinal Attributes, and SAR insights.

Protein tyrosine phosphatases (PTPs) are the class of dephosphorylation enzymes that catalyze the removal of phosphate groups from tyrosine residues on proteins responsible for various cellular processes. Any disbalance in signal pathways mediated by PTPs leads to various disease conditions like diabetes, obesity, cancers, and autoimmune disorders. Amongst the PTP superfamily, PTP1B, SHP2, Cdc25, and LMW-PTP have been prioritized as druggable targets for developing medicinal agents. PTP1B is an intracellular PTP enzyme that downregulates insulin and leptin signaling pathways and is involved in insulin resistance and glucose homeostasis. SHP2 is involved in the RAS-MAPK pathway and T cell immunity. Cdk-cyclin complex activation occurs by Cdc25-PTPs involved in cell cycle regulation. LMW-PTPs are involved in PDGF/PDGFR, Eph/ephrin, and insulin signaling pathways, resulting in certain diseases like diabetes mellitus, obesity, and cancer. The signaling cascades of PTP1B, SHP2, Cdc25, and LMW-PTPs have been described to rationalize their medicinal importance in the pathophysiology of diabetes, obesity, and cancer. Their binding sites have been explored to overcome the hurdles in discovering target selective molecules with optimum potency. Recent developments in the synthetic molecules bearing heterocyclic moieties against these targets have been explored to gain insight into structural features. The elaborated SAR investigation revealed the effect of substituents on the potency and target selectivity, which can be implicated in the further discovery of newer medicinal agents targeting the druggable members of the PTP superfamily.

An in silico approach to investigate the theranostic potential of coumarin-derived self-immolative luminescent probes.

Till date the challenge exists in the treatments of cancer for various reasons. Most importantly, the available diagnostics are expensive with research gap for enhancing the cancer detection sensitivity. Herein, a series of coumarin-derived fluorescent theranostic probes are reported that can serve as potent anticancer agents as well as in the detection of cancer cells. The potential of these probes to efficiently block one of the well-known cancer drug targets NADPH quinone oxidoreductase-1 (NQO1) is evaluated through various pharmacokinetic methods including absorption, distribution, metabolism and excretion (ADME) properties evaluation, PASS (prediction of activity spectra for substance) algorithm along with molecular docking and dynamic simulations. Further the luminescent properties of these molecules were evaluated by investigating their electronic properties in the ground and excited states with the help of density functional theory methods. Results indicate that the proposed molecules can potentially block the NADPH (reduced form of nicotinamide adenine dinucleotide) binding site of NQO1, thereby inhibiting the activity of the enzyme to ultimately disrupt the metabolism of cancer cells.

Designing Potent Anti-Cancer Agents: Synthesis and Molecular Docking Studies of Thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine Derivatives.

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, ß-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 µM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 µM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.

Live-Cell Glycocalyx Engineering.

A heavy layer of glycans forms a brush matrix bound to the outside of all the cells in our bodies; it is referred to as the "sugar forest" or glycocalyx. Beyond the increased appreciation of the glycocalyx over the past two decades, recent advances in engineering the glycocalyx on live cells have spurred the creation of cellular drugs and novel medical treatments. The development of new tools and techniques has empowered scientists to manipulate the structures and functions of cell-surface glycans on target cells and endow target cells with desired properties. Herein, we provide an overview of live-cell glycocalyx engineering strategies for controlling the cell-surface molecular repertory to suit therapeutic applications, even though the realm of this field remains young and largely unexplored.

Photo elicitation, an approach to better understanding the patient experience with OAAs: pilot study and future implications.

PURPOSE: Oral anti-cancer agents (OAAs) represent a new frontier in cancer treatment, but we do not know how well patients incorporate the strategies that they are taught for managing the side effects of OAAs into their daily lives. The purpose of this study was to understand how OAA side effects influenced patients' lives and what strategies patients used to manage them. METHODS: The study used an interpretive descriptive design utilizing photo elicitation interviews (PEI). Two pharmacists employed at the study ambulatory oncology clinic assisted with recruitment. Participants took photos and subsequent interviews focused on talking to participants about each photo, eliciting participant perspectives describing side effects of OAAs and management strategies. A directed content analysis approach was used to analyze the transcribed interviews. RESULTS: A total of nine participants were included in the study. Three themes and associated sub-themes emerged: making changes to nutritional habits due to OAA side effects (hydration and food), strategies to alleviate OAA side effects (medication and non-medication related), and methods of coping with OAA effects (intra- and interpersonal). Changing nutritional habits was an important strategy to manage OAA side effects. Medication-related strategies to alleviate OAA side effects could be nuanced and, additionally, there was wide variability in coping methods used. CONCLUSION: Patient education on OAAs and side effects is not always tailored to each unique patient and their circumstances. This study uncovered how participants devised their own distinct strategies to prevent or manage OAA side effects in an effort to help improve patients' experiences when taking OAAs.

A Bibliometric and In Silico-Based Analysis of Anti-Lung Cancer Compounds from Sea Cucumber.

Lung cancer is one of the most lethal malignancies in the world. However, current curative approaches for treating this type of cancer have some weaknesses. Therefore, scientists are attempting to discover new anti-lung cancer agents. Sea cucumber is a marine-derived source for discovering biologically active compounds with anti-lung cancer properties. To explore the anti-lung cancer properties of sea cucumber, we analyzed surveys using VOSviewer software and identified the most frequently used keywords. We then searched the Google Scholar database for compounds with anti-lung cancer properties within that keyword family. Finally, we used AutoDock 4 to identify the compounds with the highest affinity for apoptotic receptors in lung cancer cells. The results showed that triterpene glucosides were the most frequently identified compounds in studies examining the anti-cancer properties of sea cucumbers. Intercedenside C, Scabraside A, and Scabraside B were the three triterpene glycosides with the highest affinity for apoptotic receptors in lung cancer cells. To the best of our knowledge, this is the first time that anti-lung cancer properties of sea cucumber-derived compounds have been examined in in silico conditions. Ultimately, these three components displayed anti-lung cancer properties in in silico conditions and may be used for the manufacture of anti-lung cancer agents in the near future.

Exploration of potential molecular mechanisms and genotoxicity of anti-cancer drugs using next generation knowledge discovery methods.

Background & Objectives: Accurate identification of molecular and toxicological functions of potential drug candidates is crucial for drug discovery and development. This may aid in the evaluation of the risks of genotoxicity and carcinogenesis. In addition, in silico characterization of existing and new drugs might offer clues for future investigations and aid in the development of anticancer treatments. Using next-generation knowledge discovery (NGKD) methodology, we endeavored to establish a risk assessment of anticancer drugs for their molecular mechanism(s) and genotoxicity. Methods: This study was performed at the Faculty of Applied Medical Sciences, King Abdulaziz University (KAU), Jeddah, Saudi Arabia, in November 2022. Using innovative in silico model systems, we assessed the molecular mechanism of action and toxicity of around 20 distinct substances such as Deguelin, Etoposide, Camptothecin, Cytarabine (Ara-C), Cisplatin, Hydroxyurea, Trichostain A, Antimycin, Colchicine, 2-deoxyglucose, Tunicamycin, Thapsigargin, Vinblastin, Docetaxel, Oxaliplatin, Methotrexate, 5-flurouracil, Bleomycin, Taxol (Paclitaxel), and Apicidin. Using the Ingenuity Pathway Analysis (IPA) knowledge base, the number of targets for each compound was determined in silico. Subsequently, they were examined using Fisher's exact test and Benjamini Hochberg Multiple Testing Correction (P<0.05) and submitted to core analysis with IPA to decode the biological and toxicological activities differently controlled by these drugs. In addition, a multiple comparison module in IPA was used to compare the core analyses of each molecule. In addition, we obtained the top 100 protein targets of Etoposide, Camptothecin, and Ara-C using SwissTargetPrediction, as well as the key pathways and gene ontologies affected by these drugs and disease associations using the WebGestalt tool. Results: We identified distinct toxicological signatures and canonical signaling pathways in tumor cell lines regulated by these 20 anticancer drugs. These signaling pathways included cell death and apoptosis in addition to molecular processes, p53 signaling, and aryl hydrocarbon receptor signaling. The TP53 signaling pathway is utilized by these agents to effectively trigger cell death and apoptosis, and p53 functions as a master regulator in a variety of cellular stress responses, including genotoxic stress. Conclusion: Our research has laid the groundwork for the discovery of additional biomarkers that assess both the safety and effectiveness of treatment. Our mechanism based "NGKD" tools have more relevance for the identification of safer therapies and has the potential to lead to the rational screening of drug candidates targeting specific molecular networks and canonical pathways implicated in cancer and genotoxicity. In addition, the combination of protein, microRNA and metabolome profiles may be essential for the development of translatable biomarkers for the safety and efficacy of pharmacotherapeutic agents.Our research has laid the groundwork for the discovery of additional biomarkers that assess both the safety and the effectiveness of a treatment.

Ceftazidime and cefepime antagonize 5-fluorouracil's effect in colon cancer cells.

BACKGROUND: Drug-drug interaction (DDI), which can occur at the pharmacokinetics and/or the pharmacodynamics (PD) levels, can increase or decrease the therapeutic or adverse response of a drug itself or a combination of drugs. Cancer patients often receive, along their antineoplastic agents, antibiotics such as ß-lactams to treat or prevent infection. Despite the narrow therapeutic indices of antibiotics and antineoplastic agents, data about their potential interaction are insufficient. 5-fluorouracil (5-FU), widely used against colon cancer, is known for its toxicity and large intra- and inter- individual variability. Therefore, knowledge about its interaction with antibiotics is crucial. METHODS: In this study, we evaluated at the PD levels, against HCT-116 colon cancer cells, DDI between 5-FU and several ß-lactams (ampicillin, benzypenicillin, piperacillin, meropenem, flucloxacillin, ceftazidime (CFT), and cefepime (CFP)), widely used in intensive care units. All drugs were tested at clinically achieved concentrations. MTT assay was used to measure the metabolic activity of the cells. Cell cycle profile and apoptosis induction were monitored, in HCT-116 and DLD-1 cells, using propidium iodide staining and Caspase-3/7 activity assay. The uptake of CFT and CFP by the cells was measured using LC-MS/MS method. RESULTS: Our data indicate that despite their limited uptake by the cells, CFT and CFP (two cephalosporins) antagonized significantly 5-FU-induced S-phase arrest (DLD-1 cells) and apoptosis induction (HCT-116 cells). Remarkably, while CFP did not affect the proliferation of colon cancer cells, CFT inhibited, at clinically relevant concentrations, the proliferation of DLD-1 cells via apoptosis induction, as evidenced by an increase in caspase 3/7 activation. Unexpectedly, 5-FU also antagonized CFT's induced cell death in DLD-1 cells. CONCLUSION: This study shows that CFP and CFT have adverse effects on 5-FU's action while CFT is a potent anticancer agent that inhibits DLD-1 cells by inducing apoptotic cell death. Further studies are needed to decipher the mechanism(s) responsible for CFT's effects against colon cancer as well as the observed antagonism between CFT, CFP, and 5-FU with the ultimate aim of translating the findings to the clinical settings.

Optimization of the production process for the anticancer lead compound illudin M: downstream processing.

BACKGROUND: Secondary metabolites have played a key role as starting points for drug development programs due to their often unique features compared with synthetically derived molecules. However, limitations related to the discovery and supply of these molecules by biotechnological means led to the retraction of big pharmaceutical companies from this field. The reasons included problems associated with strain culturing, screening, re-discovery, purification and characterization of novel molecules from natural sources. Nevertheless, recent reports have described technical developments that tackle such issues. While many of these reports focus on the identification and characterization of such molecules to enable subsequent chemical synthesis, a biotechnological supply strategy is rarely reported. This may be because production processes usually fall under proprietary research and/or few processes may meet the requirements of a pharmaceutical development campaign. We aimed to bridge this gap for illudin M-a fungal sesquiterpene used for the development of anticancer agents-with the intention to show that biotechnology can be a vital alternative to synthetic processes dealing with small molecules. RESULTS: We used µL-scale models to develop an adsorption and extraction strategy for illudin M recovery from culture supernatant of Omphalotus nidiformis and these findings were successfully transferred into lab-scale. By adsorbing and eluting the product using a fixed resin-bed we reduced the working volume by ~ 90% and removed the aqueous phase from the process. After a washing step, a highly concentrated illudin M fraction was obtained by isocratic elution with 80% methanol. The fraction was dried and extracted using a water/heptane mixture, enriching illudin M in the heptane phase. From heptane illudin M could be instantly crystalized by concentrating the solution, achieving a final purity > 95%. CONCLUSION: We have developed a robust, scalable and low-cost downstream process to obtain highly pure illudin M. By using solid phase extraction we reduced the production of solvent waste. Heptane from the final purification step could be recycled. The reduced amounts of solvents required, and the short purification time render this method a very economic and ecologic alternative to published processes.

Optimization of the production process for the anticancer lead compound illudin M: improving titers in shake-flasks.

BACKGROUND: The fungal sesquiterpenes Illudin M and S are important base molecules for the development of new anticancer agents due to their strong activity against some resistant tumor cell lines. Due to nonspecific toxicity of the natural compounds, improvement of the pharmacophore is required. A semisynthetic derivative of illudin S (Irofulven) entered phase II clinical trials for the treatment of castration-resistant metastatic prostate cancer. Several semisynthetic illudin M derivatives showed increased in vitro selectivity and improved therapeutic index against certain tumor cell lines, encouraging further investigation. This requires a sustainable supply of the natural compound, which is produced by Basidiomycota of the genus Omphalotus. We aimed to develop a robust biotechnological process to deliver illudin M in quantities sufficient to support medicinal chemistry studies and future preclinical and clinical development. In this study, we report the initial steps towards this goal. RESULTS: After establishing analytical workflows, different culture media and commercially available Omphalotus strains were screened for the production of illudin M.Omphalotus nidiformis cultivated in a medium containing corn steep solids reached ~ 38 mg L-1 setting the starting point for optimization. Improved seed preparation in combination with a simplified medium (glucose 13.5 g L-1; corn steep solids 7.0 g L- 1; Dox broth modified 35 mL), reduced cultivation time and enhanced titers significantly (~ 400 mg L-1). Based on a reproducible cultivation method, a feeding strategy was developed considering potential biosynthetic bottlenecks. Acetate and glucose were fed at 96 h (8.0 g L-1) and 120 h (6.0 g L-1) respectively, which resulted in final illudin M titer of ~ 940 mg L-1 after eight days. This is a 25 fold increase compared to the initial titer. CONCLUSION: After strict standardization of seed-preparation and cultivation parameters, a combination of experimental design, empirical trials and additional supply of limiting biosynthetic precursors, led to a highly reproducible process in shake flasks with high titers of illudin M. These findings are the base for further work towards a scalable biotechnological process for a stable illudin M supply.

Design, synthesis, characterization and anticancer activity evaluation of deoxycholic acid-chalcone conjugates.

A series of deoxycholic acid-chalcone amides were synthesised and tested against the human lung cancer cell line, A549 and the cervical cancer cell line, SiHa. Among the synthesised deoxycholic acid-chalcone conjugates, some conjugates showed encouraging results as anticancer agents with good in vitro activity. More precisely, deoxycholic acid-chalcone conjugates 4b (IC50: 0.51 µM) and 4e (IC50: 0.84 µM) having 2­nitrophenyl and 3,4,5­trimethoxyphenyl groups exhibited a good activity against human cancer cell-line SiHa and while 4d (IC50: 0.25 µM) and 4b (IC50: 1.71 µM) showed better activity against A549 lung cancer cell line with respect to deoxycholic acid and chalcones. The anticancer activity of the bile acid conjugated chalcones was more than the activity of chalcone and deoxycholic acid alone. The results indicate that a bile acid conjugate strategy may be beneficial in improving the biological activity of chalcone derivatives. The enhanced activity of certain compounds may be due to their increased bioavailability.

Drugs repurposing: An approach to identify new hits against anticancer drug target TFIIH subunit p8.

Drug repositioning is one of the most effective approaches towards drug discovery and development. It involves the identification of new therapeutic indications of existing drugs. The present study evaluated several drugs for their ability to modulate activity of the p8 subunit of TFIIH complex. Negative modulation of p8 subunit activity disrupts protein-protein interactions (PPIs) among the subunits of TFIIH complex, and thereby the TFIIH-associated functions. TFIIH complex has key role in the transcription and nucleotide excision repair activity in cancerous cells. TFIIH complex has emerged as a privileged drug target in anticancer research. Out of 60 drugs, amlopipine (13), diltiazem (16), gemfibrozil (19), levocitrizine dihydrochloride (20), losartan potassium (22), clorthalidone (24), and escitalopram (28) showed interactions with subunit p8 in the ligand-protein binding and chemical shift perturbation studies. The Kd values were found to be between 0.25 and 1 mM. These drugs also caused thermal destabilization of the subunit p8 by negatively shifting the melting temperature by ≥ 2 °C. Molecular docking studies indicated the interaction of these drugs with important residues of p8-p52 complex, such as Glu48, Lys51, Glu496, and Glu455 via non-covalent interactions. This study has thereby identified 7 drugs that can be investigated further as potential anticancer drugs.

An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold.

[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies.

Tubulin inhibitory activity of a novel colchicine-binding compounds based on a dinaphthospiropyranran scaffold.

Spiropyrans have been investigated for their thermo- and photochromic characteristics, but their biotherapeutic properties have not been addressed. We report anti-proliferative properties of a novel dinaphthospiropyran analogue (1). The compound 1 was synthesized by a simple and expedient method using a one-pot acid-catalyzed aldol condensation of 2-hydroxy-1-naphthaldehyde with 4-piperidone followed by an acetalization reaction. Compound 1 was submitted to anticancer drug screen in the National Cancer Institute's panel of 60 human tumor cell lines. The average concentration of 1 to inhibit 50% cell growth was 5.4 ± 0.23 µM. All cell lines responded at almost the same concentration, suggesting that the action of 1 is not selective for cancer of origin. COMPARE analysis of dose-response data revealed interaction with tubulin as the possible mechanism of action of 1. At molecular level, 1 induced tubulin reorganization in colon cancer HCT-116 cells. Under cell-free conditions, the efficacy of 1 to inhibit tubulin polymerization was comparable to that of paclitaxel and vinblastine. Molecular docking showed that compound 1 binds to the colchicine-binding site of tubulin. We conclude that dinaphthospiropyrans present a novel scaffold for the development of tubulin inhibitors.

Identification of new lead molecules against anticancer drug target TFIIH subunit P8 using biophysical and molecular docking studies.

The identification of molecules, which could modulate protein-protein interactions (PPIs), is of primary interest to medicinal chemists. Using biophysical methods during the current study, we have screened 76 compounds (grouped into 16 mixtures) against the p8 subunit of the general transcription factor (TFIIH), which has recently been validated as an anti-cancer drug target. 10% of the tested compounds showed interactions with p8 protein in STD-NMR experiments. These results were further validated by molecular docking studies where interactions between compounds and important amino acid residues were identified, including Lys20 in the hydrophobic core of p8, and Asp42 and 43 in the ß3 strand. Moreover, these compounds were able to destabilize the p8 protein by negatively shifting the Tm (≥2 °C) in thermal shift assay. Thus, this study has identified 8 compounds which are likely negative modulators of p8 protein stability, and could be further considered as potential anticancer agents.

Applications and challenges in therapeutic drug monitoring of cancer treatment: A review.

Most anticancer agents show wide variability in pharmacokinetics (PK) and have a narrow therapeutic index which makes fixed dosing suboptimal. To achieve the best therapeutic outcomes with these agents, many studies have postulated using PK or therapeutic drug monitoring (TDM)-guided dosing. However, multiple factors contribute to the variability in PKs making the application of TDM in practice challenging. Also, despite the known association with clinical outcomes, standard guidelines on PK-guided dosing are lacking for most agents. Understanding the factors that contribute to PK variability and their impact is essential for dose individualization. The purpose of this review is to discuss the factors that contribute to the PK variability of anticancer agents and the challenges faced in practice when individualizing doses for certain widely used agents. Searching the literature has identified several gaps and efforts are needed to ensure better targeting of cancer therapeutics.