Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation.

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC50) values of 2.7-63 µM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC50 of 2.0 and 0.9 µM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC50 = 1.7 µM). Notably, 6c inhibited both kinases, with IC50 values of 2.7 and 3.0 µM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.

Management of Pulmonary Toxicities Associated with Systemic Therapy in Non Small Cell Lung Cancer.

OPINION STATEMENT: Drug-induced pneumonitis is a common adverse event that may occur during lung cancer systemic therapy. The incidence/prevalence of this side effect has increased due to recent extensive use of immunotherapy. Although pneumonitis prevalence is increased with the use of immune checkpoint inhibitors, it is also associated with chemotherapy and targeted therapy. Pneumonitis can occur early after drug exposure or present after several cycles of treatment. Its severity can range from insidious to fulminant, leading to hospitalization. In most cases, the diagnosis is made based on medical history, temporal correlation with use of lung cancer systemic therapy, and computed tomography (CT) findings. In the majority of cases, stopping the offending drug and use of corticosteroids is the sufficient treatment; however, patients with more severe forms of pneumonitis require additional immunosuppressive agents. In this review, we address pneumonitis caused by chemotherapy, antibody-drug conjugates, targeted therapy, or immunotherapy, and provide a detailed management approach.

Design, synthesis and biological evaluation of structurally new 4-indolyl quinazoline derivatives as highly potent, selective and orally bioavailable EGFR inhibitors.

Targeting the epidermal growth factor receptor (EGFR) has been recognized as an effective strategy for treating non-small-cell lung cancer (NSCLC). Although several representative EGFR inhibitors have been approved for clinical use, it is highly desirable to develop highly potent and selective EGFR inhibitors with novel scaffolds because of the occurrence of acquired resistance after treatment. Here we first demonstrate that the 4-indolyl quinazoline derivatives could potently inhibit EGFR in vitro and in vivo, of which YS-67 effectively and selectively inhibits EGFR[WT] (IC50 = 5.2 nM), EGFR[d746-750] (IC50 = 9.6 nM) and EGFR[L858R] (IC50 = 1.9 nM). The TREEspot™ kinase interaction map further reveals the binding selectivity toward 468 kinases. YS-67 not only potently suppresses p-EGFR and p-AKT, but also effectively inhibits proliferation of A549 (IC50 = 4.1 µM), PC-9 (IC50 = 0.5 µM) and A431 cells (IC50 = 2.1 µM). YS-67 treatment also causes colony formation inhibition, arrests cell cycle progression at G0/G1 phases and induces apoptosis. More importantly, YS-67 is well tolerated in A431 xenograft model after oral administration, showing effective tumor growth suppression and low toxicity. Collectively, YS-67 represents an underexplored scaffold for developing new EGFR inhibitors.

Rational design and eco-friendly one-pot multicomponent synthesis of novel ethylidenehydrazineylthiazol-4(5H)-ones as potential apoptotic inducers targeting wild and mutant EGFR-TK in triple negative breast cancer.

A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.

Erythema dyschromicum perstans-like eruptions induced by epidermal growth factor receptor inhibitors in patients with lung cancer.

INTRODUCTION: Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition. METHODS: We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study. RESULTS: The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.

Novel 2-[thio]acetamide linked quinazoline/1,2,4-triazole/chalcone hybrids: Design, synthesis, and anticancer activity as EGFR inhibitors and apoptotic inducers.

Novel triazoloquinazolines carrying the 2-[thio]acetamide entity (4 and 5a-d) and triazoloquinazoline/chalcone hybrids incorporating the 2-[thio]acetamide linker (8a-b and 9a-f) were developed as anticancer candidates. NCI screening of the synthesized compounds at 10 µM concentration displayed growth inhibition not only up to 99.74% as observed for 9a but also a lethal effect could be achieved as stated for compounds 9c (RPMI-8226 and HCT-116) and 8b, 9a, and 9e on the HCT-116 cell line. The antiproliferative activity was determined for the chalcone series on three cell lines: RPMI-8226, HCT-116, and MCF-7. Compounds 8b, 9a, 9b, and 9f were the most active ones. To understand the mechanistic study, the inhibitory effect on the epidermal growth factor receptor (EGFR) kinase was evaluated. The results stated that the activity of compound 8b (IC50 = 0.07 µM) was near that of the reference drug erlotinib (IC50 = 0.052 µM) whereas compound 9b (IC50 = 0.045 µM) was found to be more potent than erlotinib. Both compounds 8b and 9b were selected for cell cycle analysis and apoptotic assays. Moreover, molecular docking results of the selected chalcone hybrids showed high binding scores and good binding affinities especially for 8b and 9b, which were consistent with the biological activity (EGFR).

A cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplex.

In the skin fragility disorder epidermolysis bullosa simplex (EBS), mutations in keratin 14 (K14, also known as KRT14) or keratin 5 (K5, also known as KRT5) lead to keratinocyte rupture and skin blistering. Severe forms of EBS are associated with cytoplasmic protein aggregates, with elevated kinase activation of ERK1 and ERK2 (ERK1/2; also known as MAPK3 and MAPK1, respectively), suggesting intrinsic stress caused by misfolded keratin protein. Human keratinocyte EBS reporter cells stably expressing GFP-tagged EBS-mimetic mutant K14 were used to optimize a semi-automated system to quantify the effects of test compounds on keratin aggregates. Screening of a protein kinase inhibitor library identified several candidates that reduced aggregates and impacted on epidermal growth factor receptor (EGFR) signalling. EGF ligand exposure induced keratin aggregates in EBS reporter keratinocytes, which was reversible by EGFR inhibition. EBS keratinocytes treated with a known EGFR inhibitor, afatinib, were driven out of activation and towards quiescence with minimal cell death. Aggregate reduction was accompanied by denser keratin filament networks with enhanced intercellular cohesion and resilience, which when extrapolated to a whole tissue context would predict reduced epidermal fragility in EBS patients. This assay system provides a powerful tool for discovery and development of new pathway intervention therapeutic avenues for EBS.

Persistent alteration of the skin microbiome in patients with skin rash after receiving EGFR inhibitor treatment.

The pathological mechanism responsible for EGFR inhibitor (EGFRI)-induced skin rash remains unclear. Recent studies reveal associations between skin dysbiosis and skin inflammatory diseases. This study aimed to examine whether skin dysbiosis is associated with EGFRI-induced skin rash. Bacterial swabs were taken from the forehead of 17 cancer patients at baseline and at several time points after EGFRIs initiation, as well as from 20 healthy controls. The skin microbiome was analysed using 16S rRNA sequencing. The severity of the skin rash was assessed using the rash grade. Skin surface parameters (pH, water capacitance, and sebum level) were also measured. Compared with baseline, the abundance of Cutibacterium acnes decreased in 13 of 15 cases, and that of Staphylococcus aureus, Corynebacterium spp., Staphylococcus epidermidis or Proteobacteria increased in 13 of 15 cases after EGFRIs initiation. Skin pH increased significantly in parallel with a decrease in water capacitance after EGFRI initiation. Also, the composition of the skin microbiome of patients with severe rash was significantly different from that of healthy controls. In addition, the skin dysbiosis did not return to baseline during EGFRIs treatment for >1 year. These longitudinal observations indicate that skin dysbiosis is associated with development of skin rash.

Design, synthesis and biological evaluation of novel 3,4-dihydro-2H-[1,4]oxazino [2,3-f]quinazolin derivatives as EGFR-TKIs.

Starting with our previously reported work, a novel series of 3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-derivatives were designed, synthesized and evaluated as potent EGFR tyrosine kinase inhibitors. All of the compounds showed significant inhibitory activities against EGFRwt kinase (IC50 ≤ 937.7 nM). Among them, compound 7j demonstrated the most potent inhibitory activity toward EGFRwt tyrosine kinase with IC50 value of 25.69 nM and showed good antiproliferative activities against NCI-H1563 and H1975 cells. The median cytotoxic concentration (CC50) showed that most of the tested compounds displayed almost no cytotoxicity in vitro against 16HBE cells. In view of the reported compounds activity, the structure deserves further optimization as cancer treatment agents.

Antitumor activity and mechanisms of dual EGFR/DNA-targeting strategy for the treatment of lung cancer with EGFRL858R/T790M mutation.

Dual- or multi-targeted EGFR inhibitors as single drugs can overcome EGFR inhibitor resistance and circumvent many disadvantages of combination therapy. In this work, fifteen 4-anilinoquinazoline derivatives bearing nitrogen mustard or hemi mustard moieties were designed and synthesized as dual EGFR-DNA targeting anticancer agents. Structures of target molecules were confirmed by 1H NMR, 13C NMR and HR-MS, and evaluated for their in vitro anti-proliferative activities using MTT assay. Compound 6g emerged as the most potent derivative against mutant-type H1975 cells with IC50 value of 1.45 µM, which exhibited 4-fold stronger potency than Chl/Gef (equimolar combination of chlorambucil and gefitinib). Kinase inhibition studies indicated that 6g showed excellent inhibitory effect on EGFRL858R/T790M enzyme, which was 8.6 times more effective than gefitinib. Mechanistic studies indicated that 6g induced apoptosis of H1975 cells in a dose-dependent manner and caused DNA damage. Importantly, 6g could significantly inhibit the expression of p-EGFR and its downstream p-AKT and p-ERK in H1975 cells. Molecular docking was also performed to gain insights into the ligand-binding interactions of 6g inside EGFRWT and EGFRL858R/T790M binding sites. Moreover, 6g efficiently inhibited tumor growth in the H1975 xenograft model without side effects.

Novel 4-Amino-Quinazoline moieties ligated Platinum(IV) prodrugs overcome cisplatin resistance in EGFRWT human lung cancer.

Developing bioactive axial ligands ligated platinum(IV) complexes with advantages over monotherapy and drug combinations is an efficient strategy to ameliorate the clinical defects of platinum(II) drugs. In this article, a series of 4-amino-quinazoline moieties (privileged pharmacophores of well-studied EGFR inhhibitors) ligated platinum(IV) were synthesized and evaluated for their anticancer activities. Among the complex, 17b demonstrated higher cytotoxicity against the tested lung cancer cells (including CDDP-resistant A549/CDDP cells) while lower cytotoxicity toward human normal cells than Oxaliplatin (Oxa) or cisplatin (CDDP). Mechanistic investigation demonstrated that the enhanced intracellular uptake of 17b efficiently elevated the of reactive oxygen species levels by 6.1 times more than Oxa. Detailed mechanisms of overcoming CDDP resistance revealed that 17b significantly induced apoptosis via inducing severe DNA damage, disturbing mitochondrial transmembrane potentials, efficiently disturbing EGFR-PI3K-Akt signaling transduction and activating a mitochondria-dependent apoptosis pathway. Besides, 17b significantly inhibited migration and invasion in A549/CDDP cells. In vivo tests exhibited that 17b obtained superior antitumor effect and attenuated systemic toxicity in A549/CDDP xenografts. All these results emphasized that the antitumor action of 17b differed from that of. classical platinum(II) drugs and provided a novel practical method to overcome CDDP resistance in lung cancer.

Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFRL858R/T790M with an IC50 value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC50 value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.

Benzimidazole-linked pyrazolo[1,5-a]pyrimidine conjugates: synthesis and detail evaluation as potential anticancer agents.

A library of benzimidazole briged pyrazolo[1,5-a]pyrimidine (6a-q) was designed, synthesized and subjected for evaluation for cytotoxic potential. Antiproliferative activity, ranging from 3.1-51.5 µM, was observed against a panel of cancer cell lines which included MCF-7 (breast cancer), A549 (lung cancer), HeLa (cervical cancer) and SiHa (cervical cancer). Among them, 6k, 6l, 6n and 6o have shown significant cytotoxicity and were investigated further to study their probable mechanism of action against MCF-7 cell line. Accumulation of cells at sub-G1 phase was observed in flow cytometric analysis. The detachment of cells from substratum and membrane blebbing seen under bright field microscopy supports the ability of these conjugates to induce apoptosis. Immunostaining and western blot analysis showed EGFR, p-EGFR, STAT3, and p-STAT3 significant downregulation. Western blot analysis demonstrated an elevated level of apoptotic proteins such as p53, p21, Bax, whereas a decrease in the antiapoptotic protein Bcl-2 and procaspase-9, confirming the ability of these conjugates to trigger cell death by apoptosis. EGFR kinase assay confirms the specific activity of conjugates. Molecular docking simulation study disclosed that these molecules fit well in ATP-binding pocket of EGFR. The analysis of docking poses and the atomic interactions of different conjugates rationalize the structural-activity relationship in this series. Benzimidazole-linked pyrazolo[1,5-a]pyrimidine conjugates were synthesized and evaluated for their anticancer potential. All the conjugates have significant anticancer potential. Further mechanistic studies revealed that these conjugates arrest cancer cell growth by EGFR/STAT3 inhibition.

New apoptotic anti-triple-negative breast cancer theobromine derivative inhibiting EGFRWT and EGFRT790M: in silico and in vitro evaluation.

A new theobromine-derived EGFR inhibitor (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(2,6-dimethylphenyl)acetamide) has been developed that has the essential structural characteristics to interact with EGFR's pocket. The designed compound is 2,6-di ortho methylphenyl)acetamide derivative of the well-known alkaloid, theobromine, (T-1-DOMPA). Firstly, deep DFT studies have been conducted to study the optimized chemical structure, molecular orbital and chemical reactivity analysis of T-1-DOMPA. Then, T-1-DOMPA's anticancer potentialities were estimated first through a structure-based computational approach. Utilizing molecular docking, molecular dynamics, MD, simulations over 100 ns, MM-PBSA and PLIP studies, T-1-DOMPA bonded to and inhibited the EGFR protein effectively. Subsequently, the ADMET profiles of T-1-DOMPA were computed before preparation, and its drug-likeness was anticipated. Therefore, T-1-DOMPA was prepared for the purposes of scrutinizing both the design and the results obtained in silico. The in vitro potential of T-1-DOMPA against triple-negative breast cancer cell lines, MDA- MB-231, was very promising with an IC50 value of1.8 µM, comparable to the reference drug (0.9 µM), and a much higher selectivity index of 2.6. Interestingly, T-1-DOMPA inhibited three other cancer cell lines (CaCO-2, HepG-2, and A549) with IC50 values of 1.98, 2.53, and 2.39 µM exhibiting selectivity index values of 2,4, 1.9, and 2, respectively. Additionally, T-1-DOMPA prevented effectively the MDA-MB-231cell line's healing and migration abilities. Also, T-1-DOMPA's abilities to induce apoptosis were confirmed by acridine orange/ethidium bromide (AO/EB) staining assay. Finally, T-1-DOMPA caused an up-regulation of the gene expression of the apoptotic gene, Caspase-3, in the treated MDA-MB-231cell.

Addition of epidermal growth factor receptor inhibitors to standard chemotherapy increases survival of advanced head and neck squamous cell carcinoma patients: A systematic review and meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) is among the common tumors associated with high mortality. The aim of our meta-analysis was to determine how additional anti-epidermal growth factor receptor (EGFR) therapy to standard chemotherapy affects the progression-free (PFS) and overall survival (OS) of the patients, besides the most common side effects. We used CENTRAL, MEDLINE, and Embase databases until October 26, 2020, and included 13 eligible randomized controlled trials in our systematic research. The pooled hazard ratios (HR) for the main outcomes from the original data were estimated and for the other dichotomous outcomes, odds ratios (ORs) with their 95% confidence intervals (CI) were calculated. Addition of EGFR inhibitors to conventional chemotherapy significantly decreased the death and disease progression (for PFS HR: 0.68, 95% CI: 0.55-0.81, I2  = 65.5%, p = 0.005) and mortality (for OS HR: 0.83, 95% CI: 0.72-0.94, I2  = 42.3%, p = 0.076). In the EGFR inhibitor group, we revealed an increased chance of the over Grade 3 skin rashes (OR: 4.86; 95% CI: 1.52-15.49, I2  = 2.3%, p = 0.407), and all Grade skin rashes (OR: 18.32, 95% CI: 8.07-41.60, I2  = 56.6%, p = 0.032). Despite their unwanted dermatological side effects, the addition of EGFR inhibitors is recommended to be included in advanced HNSCC therapy.

Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR.

EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study, we reported the identification of a hit compound acting as type III allosteric inhibitor of the L858R/T790M double mutant EGFR. Herein, we report the design, synthesis and in vitro testing of a series of analogues of the previously identified hit with the aim of exploring the structure-activity relationships (SAR) around this scaffold. The performed analyses allowed us to identify two compounds 15 and 18 showing improved inhibition of double mutant EGFR with respect to the original hit, as well as interesting antiproliferative activity against H1975 NSCLC cancer cells expressing double mutant EGFR. The newly discovered compounds represent promising starting points for further hit-to-lead optimisation.

Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors.

A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

Discovery of novel 4-arylamino-quinazoline derivatives as EGFRL858R/T790M inhibitors with the potential to inhibit the non-small cell lung cancers.

Three series of quinazoline derivatives (7a-j, 8a-o, 9a-l) were designed and synthesized as EGFRL858R/T790M inhibitors. Series 7a-j and 8a-o are urea and thiourea derivatives while category 9a-l contain the Michael receptor active warhead. Most of the compounds exhibited excellent anti-proliferative activity in vitro against several cancer cell lines, including non-small cell lung cancer (NSCLC) cell lines A549 and H1975, among which 14 compounds had strong antiproliferative activity against A549 and H1975 cancer cells. What's more, they also showed moderate to excellent kinase inhibitory activity against EGFRWT and EGFRL858R/T790M. 8o exhibited the best kinase inhibitory activity with IC50 values of 0.8, 2.7 nM against EGFRWT and EGFRL858R/T790M, respectively. Moreover, AO single staining and Annexin V-FITC/PI staining results also indicated that both 8o and 9b significantly induced apoptosis in A549 cells. 8o arrested the cell cycle at S phase and 9b arrested the cell cycle at G1 phase.

Novel third-generation pyrimidines-based EGFR tyrosine kinase inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer.

The critical T790M secondary mutation in epidermal growth-factor receptor (EGFR) mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Herein, we identified 12 new 2,4-diaryl pyrimidine derivatives containing thiophene fragments as new selective third-generation EGFR inhibitors. Among them, Compound 6a showed good inhibitory activity against EGFR mutant cells with an IC50 value of 0.0022 ± 0.001 µM and was approximately 1730-fold less potent against EGFR WT cells (IC50: 4.499 ± 0.057 µM). Moreover, it strongly affected EGFR-mediated signaling pathways, attenuated tumor proliferation via the intrinsic mitochondrial apoptotic pathway, arrested the cell cycle at G0/G1 phase, and induced apoptosis in H1975 cells. It also displayed appropriate pharmacokinetic (PK) parameters with an oral bioavailability value of 33.57%. Additionally, in vivo studies confirmed that 6a suppressed tumor growth in an H1975 xenograft model (25 mg/kg/d, TGI: 90.24%). Overall, these results suggest that 6a could be a promising lead compound for overcoming the clinical EGFR T790M resistance of patients with non-small-cell lung cancers (NSCLCs).