Anti-prostate Cancer Agents Research Articles

Network pharmacology, molecular docking, and in vitro study on Aspilia pluriseta against prostate cancer

BackgroundCurrent prostate cancer treatments are associated with life-threatening side effects, prompting the search for effective and safer alternatives. Aspilia pluriseta Schweinf. ex Engl. has previously shown anticancer activity in lung and liver cancer cell lines. This study investigated its potential for prostate cancer.MethodsA crude extract of A. pluriseta root was prepared using dichloromethane/methanol (1:1 v/v) and partitioned into hexane, ethyl acetate, and water fractions. The MTT assay was used to assess the antiproliferative activity of the fractions. The active fractions were tested at 6.25–200 µg/ml on human prostate cancer DU-145 cells and non-cancerous Vero E6 cells. Qualitative phytochemical and gas chromatography-mass spectrometry (GC-MS) analyses were conducted to identify chemical compounds. Network pharmacology was employed to predict molecular targets and modes of action of the identified chemical compounds, with subsequent validation through molecular docking and real-time PCR.ResultsActive extracts included crude dichloromethane/methanol, hexane, and ethyl acetate fractions, inhibiting DU-145 cell proliferation with IC50 values of 16.94, 20.06, and 24.14 µg/ml, respectively. Selectivity indices were determined to be 6.04 (crude), 3.62 (hexane), and 6.68 (ethyl acetate). Identified phytochemicals comprised phenols, terpenoids, flavonoids, tannins, sterols, and saponins. GC-MS analysis revealed seventy-nine (79) compounds, with seven (7) meeting ideal drug candidate parameters; their hub gene targets included MAPK3, MAPK1, IL6, TP53, ESR1, PTGS2, MMP9, MDM2, AR, and MAP2K1, implicating regulation of PI3K/Akt, MAPK, and p53 signaling pathways as potential modes of action. Core compounds such as 1-heneicosanol, lanosterol, andrographolide, and retinoic acid exhibited strong binding activities, particularly lanosterol with MAPK21 (-9.7 kcal/mol), ESR1 (-8.9 kcal/mol), and MAPK3 (-8.8 kcal/mol). Treatment with A. pluriseta downregulated AR expression and upregulated p53, while also downregulating CDK1 and BCL-2 and upregulating caspase-3.ConclusionsA. pluriseta extracts inhibited DU-145 cell growth without causing cellular toxicity, suggesting great potential for development as an anti-prostate cancer agent. However, further in vitro and in vivo experiments are recommended.

Amino polycarboxylic acids-modified abiraterone derivatives as potential injectable anti-prostate cancer agents

Abiraterone (Abi), an effective cytochrome oxidase P450 C17 (CYP17) inhibitor, inhibits androgen synthesis in testes, adrenal glands, and prostate tumors. However, their low bioavailability and dissolution rate due to their poor solubility and toxic side effects have hindered their clinical applications. In this study, water-soluble and injectable Abi derivatives were developed by introducing amino polycarboxylic acids into Abi, and their antiproliferation effects in vitro, mechanism of action, antitumor activities in vivo, pharmacokinetics, and toxicity were investigated. Compared to Abi, the water-soluble derivative Abi-DTPA exhibited excellent antitumor activity in vitro and in vivo. It decreased cell migration, invasion, and mitochondrial membrane potential. A mechanistic study revealed that it still targeted the CYP17 enzyme and increased the expression levels of apoptosis-related proteins, including cleaved caspase 9, cleaved PARP, and cleaved caspase 3. Abi-DTPA was the main form in the plasma and exhibited lower toxicity after intravenous administration. These findings suggest that Abi-DTPA can be used as a novel injectable anti-prostate cancer agent.

Halogenated 2,4-diphenyl indeno[1,2-B]pyridinol derivatives as potential inhibitors of the androgen receptor (PDB ID: 58TE): A study of QSAR modeling, molecular docking, and pharmacokinetics for prostate cancer treatment

The present research was centered on the development of a predictive model aimed at assessing the responses of prostate tumors to a range of compounds within the scope of the pIC50 project. Our approach involved the utilization of a quantitative structure-activity relationship (QSAR) methodology, incorporating a genetic algorithm (GA) and multiple linear regression analyses (MLRA) applied to a dataset comprising 128 derivatives. The resultant model demonstrated a robust predictive capacity, supported by Remarkable internal and external validation metrics (R² = 0.9143 for internal consistency and R²ext. = 0.9523 for external validation), thus indicating its reliability in prognosis of tumor responses. Additionally, molecular docking simulations yielded valuable insights into the interactions between the ligands and target proteins, highlighting the significance of specific amino acid residues in the binding mechanism. These interactions were characterized by hydrogen bonds, halogen bonds, and pi-cation interactions, pointing to a substantial binding affinity with a score of −10.9 kJ/mol. The comprehensive molecular understanding obtained, including the critical role of ligand functional groups in determining interaction types, pointing out the utility of the model in identifying potential therapeutic agents. Furthermore, the study highlighted the modulation of the androgen receptor as an essential target in the treatment of prostate cancer. Molecular docking highlighted important interactions that can inform the design of novel anti-prostate cancer agents. Through the application of GA-MLR techniques, the study not only confirmed the efficacy of the predictive model in understanding prostate cancer responses but also showcased the potential of QSAR modeling in advancing prostate cancer research. The outcomes furnish a solid basis for further exploration of therapeutic compounds, emphasizing the intricate interplay between molecular structure and biological activity in the domain of drug development.

Exploring highly selective polymethoxy fenamate isosteres as novel anti-prostate cancer agents: Synthesis, biological activity, molecular docking, molecular dynamics, and ADME studies

In this study, we synthesized and characterized sixteen new polymethoxy-substituted hydrazone derivatives. These compounds were evaluated for their in vitro cytotoxic activity against human prostate cancer (PC3) and human umbilical vein endothelial (HUVEC) cell lines. Compounds 5, 6, 7, and 11 exhibited significant cytotoxic effects with high selectivity index. Molecular docking studies and MM-GBSA binding free energy calculations were performed against tubulin protein. Compound 7 emerged as a particularly promising candidate, displaying an IC50 value of 1.49 µM against PC3 cells and a selectivity index of 264. Compound 7 achieved impressive docking score -13.655 kcal/mol against tubulin and formed stable hydrogen bonds and π-π stacking interactions with key residues in this protein. MD simulations confirmed the stability of the 7-tubulin complex. ADME analysis indicated that compound 7 has favorable absorption, solubility, and permeability properties, with minimal rule violations. The SAR analysis highlighted the significance of specific functional groups in enhancing the compound's cytotoxic and binding properties. Overall, compound 7 is identified as a leading candidate due to its exceptional cytotoxicity, high selectivity index, strong binding affinities, and favorable pharmacokinetic profile, making it a top candidate for further investigation and development as a novel anticancer agent.

Synthesis and Biological Evaluation of Methoxypolyethylene-Glycol-Substituted Abiraterone Derivatives as Potential Antiprostate Cancer Agents.

Globally, prostate cancer is the most commonly diagnosed tumor and a cause of death in older men. Abiraterone, an orally administered irreversible CYP17 inhibitor, is employed to treat prostate cancer. However, abiraterone has several clinical limitations, such as poor water solubility, low dissolution rate, low bioavailability, and toxic side effects in the liver and kidney. Therefore, there is a need to identify high-efficiency and low-toxicity water-soluble abiraterone derivatives. In this work, we aimed to design and synthesize a series of abiraterone derivatives by methoxypoly(ethylene glycol) (mPEG) modification. Their antitumor activities and toxicology were analyzed in vitro and in vivo. The most potent compound, 2e, retained the principle of action on the CYP17 enzyme target and significantly improved the abiraterone water solubility, cell permeability, and blood safety. No significant abnormalities were observed in toxicology. mPEG-modification significantly improved abiraterone's antitumor activity and efficiency while reducing the associated toxic effects. The finding will provide a theoretical basis for future clinical application of mPEG-modified abiraterone.

Synthesis of new Nilutamide-pyrazole derivatives as VEGFR-2 targeting anti-prostate cancer agents

Synthesis of new Nilutamide-pyrazole derivatives as VEGFR-2 targeting anti-prostate cancer agents

Comprehensive Review on Recent Strategies for Management of Prostate Cancer: Therapeutic Targets and SAR.

Prostate cancer is a disease that is affecting a large population worldwide. Androgen deprivation therapy (ADT) has become a foundation for the treatment of advanced prostate cancer, as used in most clinical settings from neo-adjuvant to metastatic stage. In spite of the success of ADT in managing the disease in the majority of men, hormonal manipulation fails eventually. New molecules are developed for patients with various hormone-refractory diseases. Advancements in molecular oncology have increased understanding of numerous cellular mechanisms which control cell death in the prostate and these insights can lead to the development of more efficacious and tolerable therapies for carcinoma of the prostate. This review is focused on numerous therapies that might be a boon for prostate therapy like signaling inhibitors, vaccines, and inhibitors of androgen receptors. Along with these, various bioactive molecules and their derivatives are highlighted, which act as potential antiprostate cancer agents. This article also emphasized the recent advances in the field of medicinal chemistry of prostate cancer agents.

Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

Exploring substituted 3,4-dihydropyrimidinone and thione derivatives as anti-prostate cancer agents: Computational screening, synthesis, characterization, and in vitro efficacy assessment

Despite decades of research, anticancer medication therapy is still largely constrained to prevent growth and limit the spread of tumour cells. To speed up the process of finding anticancer drugs, exploring novel therapeutic macromolecules and identifying the right small molecules using an integration of computational and experimental approaches is a recent tactic adopted by investigators. In the present study, we designed and created a library of 200 ligands with 3,4-dihydropyrimidinones or their thiones linked with imidazolidinones through amide linkage and explored the extent of their in vitro anticancer activity towards human topoisomerase IIalpha (TOP2α or TOP2A) using DU-145 and PC-3 prostate cancer cell lines using the SRB assay method. This was accomplished by the molecular docking and synthesis of the titled compounds using a series of organic nucleophilic addition reactions, including the Biginelli one-pot condensation reaction. The preliminary physical character evaluation was employed for the synthesized compounds, and the structural parameters were analyzed using FTIR, proton NMR, 13C NMR, and LC-MS/MS. The anti-prostate cancer activity of the prepared Biginelli analogues was evaluated against cancer cell lines and mild-to-moderate reduction in the viability of cell lines was observed with compounds 5, 6, 9, 14, 15, 16, 17, and 19. Among them, compounds 5, 14, 15, and 16 exhibited significant potent activity against TOP2α or TOP2A. This result indicated that the derivatives of Biginelli (3,4-dihydropyrimidinones/thiones) could be promising anti-prostate cancer drug candidates.

Retraction: Design, synthesis, and biological evaluation of (E)-N'-((1-chloro-3,4-dihydronaphthalen-2-yl)methylene)benzohydrazide derivatives as anti-prostate cancer agents.

[This retracts the article DOI: 10.3389/fchem.2019.00474.].

Retraction: Corrigendum: Design, synthesis, and biological evaluation of (E)-N'-((1-chloro-3,4-dihydronaphthalen-2-yl)methylene)benzohydrazide derivatives as anti-prostate cancer agents.

[This retracts the article DOI: 10.3389/fchem.2019.00804.].

Design, Synthesis, and Biological Evaluation of Anti-prostate Cancer Agent

In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer. The 1,3- thiazolidine-2,4-diones possess a wide diversity of important biochemical effects and interesting pharmacological properties. 1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner-Wadsworth-Emmons reaction. The cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents.

Discovery and biological evaluation of novel CARM1/HDAC2 dual-targeting inhibitors with anti-prostate cancer agents

Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro. Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC50 = 3.71 ± 0.11 nM) and HDAC2 (IC50 = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC50 < 1 µM). In vivo, assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.

In-silico activity prediction and docking studies of some flavonol derivatives as anti-prostate cancer agents based on Monte Carlo optimization

The QSAR models are employed to predict the anti-proliferative activity of 81 derivatives of flavonol against prostate cancer using the Monte Carlo algorithm based on the index of ideality of correlation (IIC) criterion. CORAL software is employed to design the QSAR models. The molecular structures of flavonols are demonstrated using the simplified molecular input line entry system (SMILES) notation. The models are developed with the hybrid optimal descriptors i.e. using both SMILES and hydrogen-suppressed molecular graph (HSG). The QSAR model developed for split 3 is selected as a prominent model ({R}_{Validation}^{2}= 0.727, {IIC}_{validation}= 0.628, {Q}_{Validation}^{2}= 0.642, and {overline{r} }_{m}^{2}=0.615). The model is interpreted mechanistically by identifying the characteristics responsible for the promoter of the increase or decrease. The structural attributes as promoters of increase of pIC50 were aliphatic carbon atom connected to double-bound (C…=…, aliphatic oxygen atom connected to aliphatic carbon (O…C…), branching on aromatic ring (c…(…), and aliphatic nitrogen (N…). The pIC50 of eight natural flavonols with pIC50 more than 4.0, were predicted by the best model. The molecular docking is also performed for natural flavonols on the PC-3 cell line using the protein (PDB: 3RUK).

Design, synthesis, and docking studies of novel pyrazole-based scaffolds and their evaluation as VEGFR2 inhibitors in the treatment of prostate cancer.

Since VEGFR-2 plays a crucial role in tumor growth, angiogenesis, and metastasis, it is a prospective target for cancer treatment. In this work, a series of 3-phenyl-4-(2-substituted phenylhydrazono)-1H-pyrazol-5(4H)-ones (3a-l) were synthesized and investigated for their cytotoxicity against the PC-3 human cancer cell line compared to Doxorubicin and Sorafenib as reference drugs. Two compounds 3a and 3i showed comparable cytotoxic activity with IC50 values of 1.22 and 1.24 μM compared to the reference drugs (IC50 = 0.932, 1.13 μM). Compound 3i was found to be the most effective VEGFR-2 inhibitor using in vitro testing of the synthesized compounds, with nearly 3-fold higher activity than Sorafenib (30 nM), with IC50 8.93 nM. Compound 3i significantly stimulated total apoptotic prostate cancer cell death 55.2-fold (34.26% compared to 0.62% for the control) arresting the cell cycle at the S-phase. The genes involved in apoptosis were also impacted, with proapoptotic genes being upregulated and antiapoptotic Bcl-2 being downregulated. These results were supported by docking studies of these two compounds within the active site of the VEGFR2 enzyme. Finally, in vivo, the study revealed the potentiality of compound 3i to inhibit tumor proliferation by 49.8% reducing the tumor weight from 234.6 mg in untreated mice to 83.2 mg. Therefore, 3i could be a promising anti-prostate cancer agent.

Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents.

Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3β-hydroxy-5-ene steroids, containing an isoxazole fragment in their side chain, was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17α-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound, 24j (17R)-17-((3-(2-hydroxypropan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3β-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and the androgen receptor was confirmed and described by molecular docking.

New NNN pincer copper complexes as potential anti-prostate cancer agents

Eleven novel NNN Cu(II) complexes supported by a tridentate bis(imidazo[1,2-α]pyridin-2-yl)pyridine ligand were synthesized and characterized by elemental analysis, HRMS, and X-ray determination. Target prediction and docking studies indicated that these pincer complexes formed hydrogen bonds with Asp33 and Gly35 of Cathepsin D protein, which is highly associated with prognosis of advanced prostate cancer. Furthermore, they exhibited anti-proliferation activity in both androgen-sensitive and androgen-insensitive prostate cancer cells according to WST-1 assay results. Mechanistic study showed that pincer complexes arrested cell cycle progression at G0/G1 phase and inhibited Cathepsin D regulated signaling pathways. Most importantly, new pincer copper complexes significantly inhibited xenograft prostate cancer growth along with a promising in vivo safety profile. In summary, these results suggest the applicability of the developed novel pincer copper complexes as promising anticancer agents for prostate cancer treatment.

Abstract 690: An anti-leprosy drug, clofazimine, targets Wnt/β-catenin pathway in cadmium-transformed benign prostatic hyperplasia cells

Abstract Prostate cancer (PCa) is one of the most prevalent cancers among men in America, being second only to skin cancer. Every year 1.6 million men are diagnosed with PCa and 366,000 men die of PCa. PCa is associated to various risk factors that include old age, ethnicity, family history, lifestyle, diet, environmental and occupational exposures. Cadmium (Cd), a well-known metal carcinogen is one of the most copious occupational and environmental pollutant found in air, soil, dietary products, and tobacco. Cd is implicated in the carcinogenesis of PCa, but the mechanism remains elusive. To explore new targets for Cd induced PCa, chronic exposure of 10µM of Cd for over a year induced malignant transformation of benign prostatic hyperplasia (BPH1) cells which was used as a cellular model in this study. The Cd transformed BPH1 cells named as BPH-Cd were confirmed for tumorigenic characteristics by performing clonogenic assay, spheroid growth assay and wound healing experiments. BPH-Cd cells were further subjected to genomic analysis to identify signaling networks that are deregulated in the carcinogenesis of Cd. Our data suggested that one of the potential underlying mechanism of Cd carcinogenesis may be due to the upregulation of Wnt-3A and β-catenin pathway. In addition, Cd also activated stemness-related genes such as ALDHA1, NANOG and Oct1. Next, to determine whether targeting Wnt/β-catenin pathway in BPH-Cd could disrupt the oncogenic potential of these cells, Clofazimine, a FDA-approved anti-leprosy drug known to inhibit broad range of Wnt-dependent cancers were explored in this study. Cell viability assay indicated the inhibition of cell growth of BPH-Cd cells by Clofazimine in a dose-dependent manner with an IC50 value of 5µM. Furthermore, Clofazimine robustly inhibited the tumorigenesis of BPH-Cd as observed in colony formation assay. Of note, In-vitro 3D spheroid assay suggested that Clofazimine decreased the size of spheroids with increasing doses. Clofazimine also showed cell cycle arrest by flow cytometry in G2/M phase in BPH-Cd cells. Confocal imaging of Wnt-3A suggested a decrease in the intensity of expression with increasing doses of clofazimine in BPH-Cd treated cells. Western blot analysis of Clofazimine treated BPH-Cd cells showed downregulation of CDK2, increase in cleaved PARP-1 and upregulation of p21. Importantly, Clofazimine also displayed potent anti-cancer effects on hormone driven (androgen-dependent) LNCaP human prostate cancer cells by inhibiting the cell viability, clonogenic ability and inducing G2/M cell cycle arrest in this cell line. Taken together, our study suggests that Clofazimine could be a potential chemopreventive and anti-prostate cancer agent which warrants further evaluation for its clinical application. Citation Format: Rifika Jain, Gnanasekar Munirathinam. An anti-leprosy drug, clofazimine, targets Wnt/β-catenin pathway in cadmium-transformed benign prostatic hyperplasia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 690.

Insights into Aptamer-Drug Delivery Systems against Prostate Cancer.

Prostate cancer is a common cancer in elderly males. Significant progress has been made in the drug therapies for prostate cancer in recent years. However, side effects are still problems that have not been overcome by the currently used anti-prostate cancer drugs. Novel technologies can be applied to reduce or even eliminate the side effects of drugs. An aptamer may be a sequence of nucleic acids or peptides that can specifically recognize proteins or cells. Taking advantage of this feature, scientists have designed aptamer–drug delivery systems for the development of anti-prostate cancer agents. Theoretically, these aptamer–drug delivery systems can specifically recognize prostate cancer cells and then induce cell death without attacking normal cells. We collected the relevant literature in this field and found that at least nine compounds have been prepared as aptamer–drug delivery systems to evaluate their precise anti-prostate cancer effects. However, the currently studied aptamer–drug delivery systems have not yet entered the market due to defects. Here, we analyze the published data, summarize the characteristics of these delivery systems, and propose ways to promote their application, thus promoting the development of the aptamer–drug delivery systems against prostate cancer.

Network Pharmacology with Experimental Investigation of the Mechanisms of Rhizoma Polygonati against Prostate Cancer with Additional Herbzymatic Activity.

A combination therapy of RhizomaPolygonati (RP) with goji (Lycium chinense) has earned a long history in the prescriptions to promote male health. However, the mechanisms at both molecular and nanoscale quantum levels are unclear. Here, we found that processed RP extract induces apoptosis and cell cycle arrest in cancer cells, thereby inhibiting prostate cancer cell proliferation enhanced by processed goji extract associated with an augment of the nanoscale herbzyme of phosphatase. For network pharmacology analysis, RP-induced PI3K-AKT pathways are essential for both benign prostatic hyperplasia and prostate cancer, and the RP/goji combination induces potent pathways which include androgen and estrogen response, kinase regulation, apoptosis, and prostate cancer singling. In addition, the experimental investigation showed that the prostate cancer cells are sensitive to RP extract for inhibiting colony formation. Finally, the natural compound baicalein found in RP ingredients showed a linked activity of top-ranked signaling targets of kinases including MAPK, AKT, and EGFR by the database of cMAP and HERB. Thus, both the nanozyme and ingredients might contribute to the RP in anti-prostate cancer which can be enhanced by goji extract. The proposed nanoscale RP extract might be of significance in developing novel anti-prostate cancer agents by combining goji compositions and targeted therapy compounds.