RESUMEN

MET amplification (METamp) represents a promising therapeutic target in non-small cell lung cancer, but no consensus has been established to identify METamp-dependent tumors that could potentially benefit from MET inhibitors. In this study, an analysis of MET amplification/overexpression status was performed in a retrospectively recruited cohort comprising 231 patients with non-small cell lung cancer from Shanghai Chest Hospital (SCH cohort) using 3 methods: fluorescence in situ hybridization (FISH), hybrid capture-based next-generation sequencing, and immunohistochemistry for c-MET and phospho-MET. The SCH cohort included 130 cases known to be METamp positive by FISH and 101 negative controls. The clinical relevance of these approaches in predicting the efficacy of MET inhibitors was evaluated. Additionally, next-generation sequencing data from another 2 cohorts including 22,010 lung cancer cases were utilized to examine the biological characteristics of different METamp subtypes. Of the 231 cases, 145 showed MET amplification/overexpression using at least 1 method, whereas only half of them could be identified by all 3 methods. METamp can occur as focal amplification or polysomy. Our study revealed that the inconsistency between next-generation sequencing and FISH primarily occurred in the polysomy subtype. Further investigations indicated that compared with polysomy, focal amplification correlated with fewer co-occurring driver mutations, higher protein expressions of c-MET and phospho-MET, and higher incidence in acquired resistance than in de novo setting. Moreover, patients with focal amplification presented a more robust response to MET inhibitors compared with those with polysomy. Notably, a strong correlation was observed between focal amplification and programmed cell death ligand-1 expression, indicating potential therapeutic implications with combined MET inhibitor and immunotherapy for patients with both alterations. Our findings provide insights into the molecular complexity and clinical relevance of METamp in lung cancer, highlighting the role of MET focal amplification as an oncogenic driver and its feasibility as a primary biomarker to further investigate the clinical activity of MET inhibitors in future studies.

Asunto(s)

RESUMEN

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have demonstrated the ability to impede tumor cell proliferation by suppressing EGFR expression. Nonetheless, patients undergoing treatment may acquire resistance, which may occur through an EGFR-dependent (such as T790M mutation) or an EGFR-independent (such as c-Met amplification) manner. Therefore, developing dual-target inhibitors might present a potential avenue for addressing treatment-acquired resistance in patients. Herein, we designed, synthesized, and screened several novel 4-phenoxyquinazoline derivatives, aiming to identify a potent dual EGFR/c-Met inhibitor for the treatment of NSCLC, among which H-22 emerged as the most promising candidate exhibiting significant antitumor properties. Moreover, we assessed the in vitro inhibitory effect of H-22 on EGFR kinase and c-Met kinase in five cancer cell lines. In addition, a series of functional experiments (cell cycle, apoptosis assays, in vitro/in vivo animal model, etc.) were conducted to further investigate the anti-tumor mechanisms of H-22. The present study revealed that H-22 exhibited strong antitumor activity both in vitro and in vivo. Interestingly, H-22 exhibited anti-proliferative activity (2.27-3.35 µM) similar to Afatinib against all five cancer cells, with inhibitory functions against EGFRWT, EGFRL858R/T790M, and c-Met kinases at a concentration of 64.8, 305.4 and 137.4 nM, respectively. Cell cycle analysis indicated that the antiproliferative activity of H-22 was associated with its ability to cause G2/M arrest. Furthermore, in vivo data showed that H-22 could inhibit tumor growth in our xenograft models and induce apoptosis. Collectively, our findings uncovered that H-22 is a novel dual EGFR and c-Met inhibitor and a prospective anti-tumor therapeutic drug.

Asunto(s)

RESUMEN

Papillary subtypes of renal-cell carcinoma (pRCC) represent 10-15% of the cases and commonly have MET alterations. This systematic review and single-arm meta-analysis evaluated MET inhibitor therapy (METi) efficacy and safety in adults with confirmed advanced pRCC. The search strategy included PubMed, Web-of-science, Cochrane, and Scopus. We used the DerSimonian/Laird random effect model for all analyses; p-value < 5% was considered significant, and heterogeneity was assessed with I2. Three clinical trials and six cohort studies were included with 504 patients; 31% were MET-driven. Our pooled analysis demonstrated an objective response rate (ORR) in MET-driven, MET-independent, and overall patients of: 36% (95%CI: 10-62), 0% (95%CI: 0-3), and 21% (95%CI: 1-41), respectively. One-year disease control and progression-free survival rates were, respectively, 70% (95%CI: 52-88) and 15% (95%CI: 10-20). Twelve- and twenty-four-month survival rates were, respectively, 43% (95%CI: 23-64) and 10% (95%CI: 0-30). The prevalence of adverse events of any grade and grades 3-5 were 96% (95%CI: 91-100) and 44% (95%CI: 37-50), respectively. We suggest METi has anti-tumor activity and is tolerable in patients with advanced pRCC.

Asunto(s)

RESUMEN

BACKGROUND: Real-World evidence on mesenchymal-epithelial transition exon 14 skipping mutations (METex14) in lung cancer remains limited. With an incidence of 3-4% across histological subtypes, METex14 is now an actionable target for MET inhibitors (METi) in advanced lung cancer, demonstrating response rates between 30-70%. Yet, its role in early stages and sensitivity to immune checkpoint inhibitors (ICIs) is still under exploration. MATERIAL AND METHODS: We conducted a retrospective analysis of the clinical data of lung cancer patients presenting with METex14 across all stages. These patients were treated at two Swedish University Hospitals: Karolinska and Skåne, between the years 2014 and 2022. RESULTS: We identified a total of 63 patients, of which 50 met the inclusion criteria. The median overall survival (OS) with corresponding 95% confidence intervals (95% CI) according to the stage was not reached (NR) for stage I, NR for stage II, 15 months (95% CI, 5.4-24.6) for stage III, and 17 months (95% CI, 9.2-NR) for stage IV. The median OS for stage IV patients who received a METi was 17 months (95% CI, 9.5-NR) vs. 10 months (95% CI, 6.2-NR) in patients without METi (p = 0.92; Hazard Ratio [HR] = 1.07). The median OS for stage IV patients who received ICIs was 18 months (95% CI, 16.5-NR) vs. 6 months (95% CI, 2.5-NR) in patients without ICIs (p = 0.15; HR = 0.47). The median OS for stage IV patients who received chemotherapy was 17 months (95% CI, 9.7-NR) vs. 10 months (95% CI, 4.5-NR) in patients without (p = 0.97; HR = 0.98). CONCLUSIONS: Our data suggest limited survival benefits from METi, ICIs, and chemotherapy for METex14 lung cancer patients. While not statistically significant, these findings underscore the need for larger trials for validation. Identifying effective treatments for this challenging lung cancer subtype remains a priority.

Asunto(s)

RESUMEN

Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the 'druggable' molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.

RESUMEN

Introduction: NSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. Methods: We reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. Results: Among 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients-the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. Conclusions: Many patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.

RESUMEN

Safety data on MET inhibitors in patients with advanced NSCLC harboring MET exon 14 mutation and treated with frontline immune checkpoint inhibitors (ICIs) are still limited. Here, we describe clinical characteristics, liver biopsy features, and management of liver injury of two patients with a diagnosis of MET exon 14-mutant NSCLC receiving capmatinib after ICI failure. On the basis of histologic findings and exclusion of other potential causes, a diagnosis of drug-induced liver injury (DILI) associated with portal fibrosis was made in both cases. The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization. To provide a global safety perspective, we queried the Food and Drug Administration Adverse Event Reporting System and detected a robust disproportionality signal. Out of the 918 total reports with capmatinib from the Food and Drug Administration Adverse Event Reporting System database, DILI was recorded in 43 cases (4.7%), mostly serious (93.0%) with hospitalization and death recorded in 25.6% and 16.3% of the cases, respectively. The median time to onset was 42 days, with discontinuation and positive dechallenge documented in 41.9% and 39.5% of the cases, respectively. Anti-programmed cell death protein-1 agents were coreported in 11 DILI cases. Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted.

RESUMEN

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.

Asunto(s)

RESUMEN

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians.
.

Asunto(s)

RESUMEN

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians.
.

Asunto(s)

RESUMEN

Background: Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway. Objectives: This study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC. Methods: We searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (I 2>50%). Safety analysis was performed based on adverse events reported in all studies. Results: Eleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]). Conclusion: MET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.

RESUMEN

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC50 value of 0.002 µM, compared to tepotinib (IC50 = 0.013 µM). Mechanistic studies revealed that compound (R, S)-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound (R, S)-12a induced cellular apoptosis and cell cycle arrest at the G1 phase in a dose-dependent fashion.

Asunto(s)

RESUMEN

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC). The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation. Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged.

Asunto(s)

RESUMEN

INTRODUCTION: The hepatocyte growth factor (HGF) receptor MET is an oncogenic driver in a subpopulation of Non-small Lung Cancer Cells (NSCLC) at the primary tumor stage or in acquired resistance to treatment with tumor-targeting tyrosine kinase inhibitors (TKIs). AREAS COVERED: This article summarizes the mechanisms leading to overexpression and activation of MET by amplification and mutations including exon 14 aberrations. Furthermore, the methods to detect and categorize MET as a tumor driver and the selective TKIs for patient treatment are discussed. EXPERT OPINION: Activating mutations and rearrangements of kinases in NSCLC are the target of successful therapeutic intervention. However, MET activation involves a number of complex alterations including gene amplification, prevention of degradation by METex14 exon skipping and a host of gene mutations. A high-level MET expression is the precondition for tumor responses to TKIs and the confirmation of MET-dependent tumor progression is difficult in primary lesions and in tumors exhibiting resistance to mutated EGFR-directed therapy in absence of standardized and concordant assays of MET amplification.

Asunto(s)

RESUMEN

c-Met inhibitors are a class of drugs that include nonselective and selective molecules. These drugs can differ in terms of pharmacodynamic and pharmacokinetic properties that may be clinically relevant. c-Met inhibitors with high potency and selectivity may allow achieving optimal c-Met inhibition in c-Met-driven tumors while reducing unwanted off-target toxicities due to activation of multiple kinases. Nonselective drugs can instead be considered in tumors that also recognize other drivers (e.g., ALK, ROS, VEGF). Improved understanding of the clinical pharmacokinetics of c-Met inhibitors can help avoid drug-drug interactions and optimize schedules for continuous in vivo inhibition of c-Met phosphorylation. The current review article provides a detailed overview of the clinical pharmacology of molecules used in c-Met-driven tumors.

Asunto(s)

RESUMEN

INTRODUCTION: c-Met tyrosine kinase receptor is a high-affinity ligand of hepatocyte growth factor (HGF). c-Met is widely expressed in a variety of normal human tissues, but shows abnormally high expression, amplification or mutation in tumour tissues such as lung, gastric and breast cancers. Therefore, the use of c-Met as a target can achieve the inhibition of a series of abnormal physiological processes such as tumourigenesis, development and metastasis. A number of small molecule tyrosine kinase inhibitors targeting c-Met have been successfully marketed. AREAS COVERED: This article reviews recent advances in patented c-Met small molecule inhibitors and their inhibitory activity against various cancer cells from 2018 to date. EXPERT OPINION: To date, small molecule inhibitors targeting c-Met have demonstrated impressive therapeutic efficacy in the clinical setting. Most recent patents have focused on addressing the direction of c-Met amplification and overexpression. Despite the great success in the development of selective c-Met inhibitors, the effects of bypass secretion and mutagenesis have led to a need for new c-Met small molecule inhibitors that are safe, efficient, selective and less toxic with novel structures and effective against other targets.

Asunto(s)

RESUMEN

In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition (MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.

Asunto(s)

RESUMEN

Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number.

RESUMEN

A quantitative structure-activity relationship (QSAR) study is performed on 48 novel 4,5,6,7-tetrahydrobenzo[D]-thiazol-2 derivatives as anticancer agents capable of inhibiting c-Met receptor tyrosine kinase. The present study is conducted using multiple linear regression, multiple nonlinear regression and artificial neural networks. Three QSAR models are developed after partitioning the database into two sets (training and test) via the k-means method. The obtained values of the correlation coefficients by the three developed QSAR models are 0.90, 0.91 and 0.92, respectively. The resulting models are validated by using the external validation, leave-one-out cross-validation, Y-randomization test, and applicability domain methods. Moreover, we evaluated the drug-likeness properties of seven selected molecules based on their observed high activity to inhibit the c-Met receptor. The results of the evaluation showed that three of the seven compounds present drug-like characteristics. In order to identify the important active sites for the inhibition of the c-Met receptor responsible for the development of cancer cell lines, the crystallized form of the Crizotinib-c-Met complex (PDB code: 2WGJ) is used. These sites are used as references in the molecular docking test of the three selected molecules to identify the most suitable molecule for use as a new c-Met inhibitor. A comparative study is conducted based on the evaluation of the predicted properties of ADMET in silico between the candidate molecule and the Crizotinib inhibitor. The comparison results show that the selected molecule can be used as new anticancer drug candidates.