Advances in the discovery of activin receptor-like kinase 5 (ALK5) inhibitors.

Activin receptor­like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-ß (TGF-ß) family. (TGF-ß) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation within the signaling pathway can cause variety of diseases, such as fibrosis, cardiovascular disease, and especially cancer, rendering ALK5 a potential drug target. Hence, various small molecules have been designed and synthesized as potent ALK5 inhibitors. In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure-activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles.

Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells.

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18-49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 µM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.

Design, molecular modelling and synthesis of novel benzothiazole derivatives as BCL-2 inhibitors.

Apoptosis plays a crucial role in cancer pathogenesis and drug resistance. BCL-2 family of enzymes is considered as one of the key enzymes which is involved in apoptosis. When there is disruption in the balance between anti-apoptotic and pro-apoptotic members of the BCL-2 family apoptosis is dysregulated in the affected cells. Herein, 33 novel benzothiazole-based molecules 7a-i, 8a-f, 9a-b, 12a-e, 13a-d, 14a,b, and 17a-j were designed, synthesized and tested for their BCL-2 inhibitory activity. Scaffold hopping strategy was applied in designing of the target compounds. Compounds 13c and 13d showed the highest activity with IC50 values equal to 0.471 and 0.363 µM, respectively. Molecular docking studies of the synthesized compounds showed comparable binding interactions with the lead compound. Structure activity relationship study was performed to show the effects of structural modifications on the inhibitory activities on BCL-2.

A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells.

Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as d-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled d-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate d-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against 18F-labeled d-fructose-based probe 6-[18F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells.

Molecular design, synthesis and biological evaluation of novel 1,2,5-trisubstituted benzimidazole derivatives as cytotoxic agents endowed with ABCB1 inhibitory action to overcome multidrug resistance in cancer cells.

Multidrug resistance (MDR) is a leading cause for treatment failure in cancer patients. One of the reasons of MDR is drug efflux by ATP-binding cassette (ABC) transporters in eukaryotic cells especially ABCB1 (P-glycoprotein). In this study, certain novel 1,2,5-trisubstituted benzimidazole derivatives were designed utilising ligand based pharmacophore approach. The designed benzimidazoles were synthesised and evaluated for their cytotoxic activity towards doxorubicin-sensitive cell lines (CCRF/CEM and MCF7), as well as against doxorubicin-resistant cancer cells (CEM/ADR 5000 and Caco-2). In particular, compound VIII showed a substantial cytotoxic effect in all previously mentioned cell lines especially in doxorubicin-resistant CEM/ADR5000 cells (IC50 = 8.13 µM). Furthermore, the most promising derivatives VII, VIII and XI were tested for their ABCB1 inhibitory action in the doxorubicin-resistant CEM/ADR 5000 subline which is known for overexpression of ABCB1 transporters. The results showed that compound VII exhibited the best ABCB1 inhibitory activity at three tested concentrations (22.02 µM (IC50), 50 µM and 100 µM) in comparison to verapamil as a reference ABCB1 inhibitor. Such inhibition resulted in a synergistic effect and a massive decrease in the IC50 of doxorubicin (34.5 µM) when compound VII was used in a non-toxic dose in combination with doxorubicin in doxorubicin-resistant cells CEM/ADR 5000 (IC50(Dox+VII) = 3.81 µM). Molecular modelling studies were also carried out to explain the key interactions of the target benzimidazoles at the ABCB1 binding site. Overall the obtained results from this study suggest that 1,2,5-trisubstituted benzimidazoles possibly are promising candidates for further optimisation and development of potential anticancer agents with ABCB1 inhibitory activity and therefore overcome MDR in cancer cells.

Osteolipoma of the ankle: A rare case report.

Osteolipoma are uncommon benign soft tissue tumors, deriving from fat cells metaplasia. We report a case of 47-year-old female with a progressively enlarging, painless mass over the anteromedial aspect of left ankle, explorations showed a calcified masse and histopathologic diagnosis was in favor of osteolipoma, which was resected surgically without any recurrence after 2 years follow up. This tumor can affect different regions of the body but ankle location is very rare and must be distinguished from other diagnosis essentially sarcoma.

Enneking type III resection of pubic chondrosarcoma: A case report.

Chondrosarcomas are rare malignant cartilaginous tumor affecting adult and elderly patient. Pelvic and long bones are the most common location. We differentiate conventional chondrosarcoma which arises do novo from preexisting normal bone (primary chondrosarcoma) or within a preexisting lesion such as enchondromas or osteochondromas (secondary chondrosarcoma), Other rare subtypes of chondrosarcoma include clear cell chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma, which will be considered separately. Although there are diverse clinical presentations depending on the anatomic extend, radiographic features of chondrosarcoma are very characteristic comprising frequently a combination of bone expansion and heterogeneous calcifications. We report a case of a 56-year-old male suffering from fixed mass adhering to the right pubic bone. MRI views showed a lytic lesion of right superior pubic rami, surgical biopsy was in favor of chondrosarcomas, then an en bloc resection was performed following a Pfannenstiel approach without any recurrence after three years of follow-up.

Synthesis and in vitro antiproliferative activity of certain novel pyrazolo[3,4-b]pyridines with potential p38α MAPK-inhibitory activity.

Novel series of pyrazolo[3,4-b]pyridines 9a-j and 14a-f were prepared via a one-pot three-component reaction. Compounds 9a-j were synthesized by the reaction of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-amine (4) with benzoyl acetonitriles 3a,b and aldehydes 5a-e, whereas the spiro derivatives 14a-f were synthesized by the reaction of pyrazole derivative 4 with 3a-c and indoline-2,3-diones 10a,b. Screening of the antiproliferative activity of 9a-j and 14a-f revealed that 14a and 14d were the most potent analogues against HepG2 and HeLa cells, with IC50 = 4.2 and 5.9 µM, respectively. Moreover, compounds 9c and 14a could promote cell cycle disturbance and apoptosis in HepG2 cells, as evidenced by DNA flow cytometry and Annexin V-FITC/PI assays. Cell cycle analysis of 9c and 14a indicated a reduction in HepG2 cells in the G1 phase, with arrest in the S phase and the G2/M phase, respectively. Also, 9c and 14a are good apoptotic inducers in the HepG2 cell line. Furthermore, compounds 9h and 14d stood out as the most efficient antiproliferative agents in the NCI 60-cell line panel screening, with mean GI % equal to 60.3% and 55.4%, respectively. Additionally, 9c, 9h, 14a, and 14d showed good inhibitory action against the cellular pathway regulator p38α kinase, with IC50 = 0.42, 0.41, 0.13, and 0.64 µM, respectively. A docking study was carried out on the p38α kinase active site, showing a binding mode comparable to that of reported p38 mitogen-activated protein kinase inhibitors. These newly discovered pyrazolo[3,4-b]pyridines could be considered as potential candidates for the development of newly targeted anticancer agents.

Metabolic Seizures.

Metabolic diseases should always be considered when evaluating children presenting with seizures. This is because many metabolic disorders are potentially treatable and seizure control can be achieved when these diseases are appropriately treated. Seizures caused by underlying metabolic diseases (metabolic seizures) should be particularly considered in unexplained neonatal seizures, refractory seizures, seizures related to fasting or food intake, seizures associated with other systemic or neurologic features, parental consanguinity, and family history of epilepsy. Metabolic seizures can be caused by various amino acids metabolic disorders, disorders of energy metabolism, cofactor-related metabolic diseases, purine and pyrimidine metabolic diseases, congenital disorders of glycosylation, and lysosomal and peroxisomal disorders. Diagnosing metabolic seizures without delay is essential because the immediate initiation of appropriate therapy for many metabolic diseases can prevent or minimize complications.

Discovery of potent thieno[2,3-d]pyrimidine VEGFR-2 inhibitors: Design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations.

Vascular endothelial growth factor receptor (VEGFR) is one of the well-known targets that control angiogenesis and cancer progression. In this study, we are reporting the design, synthesis and biological evaluation of a series of 4-substituted thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors. The design of these compounds was based on interactions extracted from crystal structure of potent pyrrolo[3,2-d]pyrimidine inhibitor VIII with VEGFR-2 (PDB: 3VHE). In addition to these interactions, the new compounds were also designed to interact with residues in the solvent accessible region such as Asn923. Accordingly, the thienopyrimidine target compounds were synthesized and subjected to VEGFR-2 enzyme inhibition assay. Several target compounds (7d-f, 8b-c, 8e-g and 15c) exhibited potent inhibitory activities against VEGFR-2 with IC50 values in low nanomolar range. Compounds 8b and 8e revealed exceptionally potent inhibitory activity with IC50 of 5 and 3.9 nM, respectively. The molecular docking analysis and molecular dynamics simulation were also performed to further investigate these findings.

Molecular design, synthesis and in vitro biological evaluation of thienopyrimidine-hydroxamic acids as chimeric kinase HDAC inhibitors: a challenging approach to combat cancer.

A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.

Epidemiology of breast cancer in women based on diagnosis data from oncologists and senologists in Algeria.

BACKGROUND: Breast cancer (BC) is a major health issue threatening women's life. No reliable epidemiological data on BC diagnosed by oncologists/senologists are available in Algeria. METHODS: The BreCaReAl study, a non-interventional prospective cohort study, included adult women with confirmed BC in Algeria. Disease incidence, patients and disease characteristics, treatment patterns, and mortality rate were recorded up to 12 months of follow-up. RESULTS: Overall, 1,437 patients were analysed: median age was 48 [41;57] years and 337 (23.5%) women had a family history of BC. BC incidence was 22.3 (95% CI: 21.5; 23.2) cases per 100,000 inhabitants over 8 months. Delayed diagnosis was reported in 400 (29.2%) patients. First line of treatments were mainly chemotherapy and surgery. Twenty-eight serious adverse events were reported including 10 (37.0%) events which led to death. Mortality rate reached 3.2% at 12 months CONCLUSION: A delayed diagnosis highlights the importance of implementing more effective screening strategies.

The Lebanese left ventricular assist device experience, a success story despite the odds.

BACKGROUND AND AIM: Heart failure is still a leading cause of mortality and morbidity. Assist devices are reserved for advanced heart failure patients with no other therapeutic options. We aim in this paper to describe the characteristics and outcome of Lebanese left ventricular assist device (LVAD) patients. RESULTS: From 2010 till December 2019, 78 patients were implanted with assist devices at the Beirut cardiac Institute, 82 pumps were used. To the most recent follow up after 10 years, 26 patients died (34%). 24 patients of 35 (68%) survived more than 5 years. Seven patients only (9%) died during one month of surgery. One year mortality was 19% (15 patients). The leading cause of early mortality was infection, whereas cerebrovascular accidents CVA were the leading cause of late mortality. Pump thrombosis occurred in 12% of the cases. The most serious long term complication was haemorrhagic CVA. Only seven patients (9%) received heart transplantation, with a mean time on support prior to transplantation of 1303 ± 213 days. CONCLUSION: In this manuscript we reported the characteristics and outcome of the largest population of LVAD patients in Lebanon. The survival rate was 81% at one year. These findings were comparable to the international registries except for rates of heart transplantation. More efforts should be made to encourage organ donation in Lebanon.

Penicillin binding protein 2a: An overview and a medicinal chemistry perspective.

Antimicrobial resistance is an imminent threat worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the "superbug" family, manifesting resistance through the production of a penicillin binding protein, PBP2a, an enzyme that provides its transpeptidase activity to allow cell wall biosynthesis. PBP2a's low affinity to most ß-lactams, confers resistance to MRSA against numerous members of this class of antibiotics. An Achilles' heel of MRSA, PBP2a represents a substantial target to design novel antibiotics to tackle MRSA threat via inhibition of the bacterial cell wall biosynthesis. In this review we bring into focus the PBP2a enzyme and examine the various aspects related to its role in conferring resistance to MRSA strains. Moreover, we discuss several antibiotics and antimicrobial agents designed to target PBP2a and their therapeutic potential to meet such a grave threat. In conclusion, we consider future perspectives for targeting MRSA infections.

Towards discovery of novel scaffold with potent antiangiogenic activity; design, synthesis of pyridazine based compounds, impact of hinge interaction, and accessibility of their bioactive conformation on VEGFR-2 activities.

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 µM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.

Design, synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors.

Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5-a][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug.

Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity.

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 µM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.

Identification of new pyrrolo[2,3-d]pyrimidines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, biological evaluation and molecular modeling.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3-d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range. Among these compounds, pyrrolo[2,3-d]pyrimidine derivatives carrying biaryl urea moieties (12d and 15c) exhibited IC50 values of 11.9 and 13.6 nM respectively. Additionally, most of the newly synthesized final compounds were tested on 60 human cancer cell lines. Docking of these compounds into the inactive conformation of VEGFR-2 was performed which showed comparable binding modes to that of the FDA approved VEGFR-2 kinase inhibitors. These newly discovered potent kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agent.

Synthesis and molecular docking studies of some novel Schiff bases incorporating 6-butylquinolinedione moiety as potential topoisomerase IIß inhibitors.

A series of novel pyranoquinolinone-based Schiff's bases were designed and synthesized. They were evaluated for topoisomerase IIß (TOP2B) inhibitory activity, and cytotoxicity against breast cancer cell line (MCF-7) for the development of novel anticancer agents. A molecular docking study was employed to investigate their binding and functional properties as TOP2B inhibitors, using the Discovery Studio 2.5 software, where they showed very interesting ability to intercalate the DNA-topoisomerase complex. Compounds 2a, 2c and 2f showed high docking score values (82.36% -29.98 kcal mol-1 for compound 2a, 78.18% -26.98 kcal mol-1 for compound 2c and 78.65, -28.11 kcal mol-1 for compound 2f) and revealed the highest enzyme inhibition activity. The best hit compounds exhibited highly potent TOP2B inhibitors with submicromolar IC50 at 5 µM compared to the reference doxorubicin.

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors.

In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC50 values of 91.7 nM and 1.2 µM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC50 values of 1.45, 3.5 and 4.83 µM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC50 of 4.2 µM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.