Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field

Primer sequences for real-time quantitative PCR.

<p>Primer sequences for real-time quantitative PCR.</p

Y20 attenuates cardiac histological abnormalities and hypertrophy in the hearts of HFD-fed rats.

<p>(A) Representative images for the Hematoxylin-Eosin (H&E) staining in the formalin-fixed myocardial tissues (400× magnification). (B) Qantitative data of myocyte cross-section lenth of 100 cells chosen from different visual scopes of 4 samples per group in myocardial transverse H&E staining were shown. (C) Western blot analysis for the protein expression of ANP in the myocardial tissues was performed. (D & E) The mRNA expression of the hypertrophic markers ANP and BNP in the myocardial tissues was detected by real-time qPCR. Four rats in each group were used for above analysis. *, <i>P</i><0.05, **, <i>P</i><0.01 v.s. HFD; # <i>P</i><0.05 v.s. vehicle control (Ctrl).</p

The design and synthesis of compound Y20.

<p>(A) The chemical structure of curcumin, C66 and Y20. (B) The chemical synthesis of Y20. Reagents and conditions: (i) 4-Methylbenzenesulfonic acid, toluene, 110℃ reflux, 4h; (ii) EtOH, 78℃, reflux, 5h, saturate HCl; (iii) 20% NaOH, EtOH, r.t., 10h.</p

Y20 mitigates HFD-induced cardiac apoptosis in HFD-fed rats.

<p>(A) Representative images and statistic figure for TUNEL staining in heart tissues sections. (B) Western Blot analysis for the protein expression of apoptosis-related proteins in myocardial tissues was performed. Four to six rats in each group were used for above analysis. * <i>P</i><0.05, ** <i>P</i><0.01 v.s. HFD group; # <i>P</i><0.05 v.s. vehicle control (Ctrl).</p

Y20 attenuates cardiac fibrosis in the hearts of HFD-fed rats.

<p>(A) Representative images for Sirius Red staining and masson staining in the formalin-fixed myocardial tissues indicating collagen deposition and implying the extent of cardiac fibrosis (400×magnification). (B) Western blot analysis for the protein expression of TGF-β in the myocardial tissues was performed. (C-F) The mRNA expression of fibrotic markers such as collagen 1, TGF-β, MMP-2 and MMP-9 in the myocardial tissues was detected by real-time qPCR. Four rats in each group were used for above analysis. * <i>P</i><0.05, ** <i>P</i><0.01 v.s. HFD group; # <i>P</i><0.05 v.s. vehicle control (Ctrl).</p

Isolinderalactone Ameliorates the Pathology of Alzheimer’s Disease by Inhibiting the JNK Signaling Pathway

Neuronal cell damage is a major cause of cognitive impairment in Alzheimer’s disease (AD). Multiple factors, such as amyloid deposition, tau hyperphosphorylation, and neuroinflammation, can lead to neuronal cell damage. Therefore, the development of multi-target drugs with broad neuroprotective effects may be an effective strategy for the treatment of AD. Natural products have become an important source of drug discovery because of their good pharmacological activity, multiple targets, and low toxicity. In this study, we screened a natural compound library and found that the fat-soluble sesquiterpene natural compound isolinderalactone (Iso) extracted from the dried root pieces of Lindera aggregata had the ability to alleviate cellular damage induced by β-amyloid-1–42 (Aβ1–42). The role and mechanism of Iso in AD have not yet been reported. Herein, we demonstrated that Iso significantly reduced the level of apoptosis in PC12 cells. Besides, Iso treatment reduced amyloid deposition, neuron apoptosis, and neuroinflammation, ultimately improving the cognitive dysfunction of APP/PS1 (APPswe/PSEN 1dE9) mice. Notably, Iso-10 mg/kg showed superior improved effects in APP/PS1 mice compared with the positive control drug donepezil-5 mg/kg. Mechanistically, the results of RNA sequencing combined with Western blots showed that Iso exerted its therapeutic effect by inhibiting the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our findings suggest that Iso is a potential drug candidate for the treatment of AD

Design, Synthesis, and Structure–Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis

Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 264.7 macrophages. A majority of these derivatives effectively inhibited lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Preliminary structure–activity relationship analysis was also conducted. The results indicate that the most promising compounds in the prepared series were <b>14f</b> and <b>14g</b>. They were found to effectively reduce LPS-induced pulmonary inflammation and overexpression of a series of inflammatory mediators. Furthermore, in vivo administration of <b>14f</b> and <b>14g</b> resulted in remarkable lung histopathological improvements in mice without toxicity in organs. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful for further treatment in inflammatory diseases

Synthesis and Anti-inflammatory Evaluation of Novel Benzimidazole and Imidazopyridine Derivatives

Sepsis, an acute inflammatory disease, remains the most common cause of death in intensive care units. A series of benzimidazole and imidazopyridine derivatives were synthesized and screened for anti-inflammatory activities, and the imidazopyridine series showed excellent inhibition of the expression of inflammatory cytokines in LPS-stimulated macrophages. Compounds <b>X10</b>, <b>X12</b>, <b>X13</b>, <b>X14</b>, and <b>X15</b> inhibited TNF-α and IL-6 release in a dose-dependent manner, and <b>X12</b> showed no cytotoxicity in hepatic cells. Furthermore, <b>X12</b> exhibited a significant protection against LPS-induced septic death in mouse models. Together, these data present a series of new imidazopyridines with potential therapeutic effects in acute inflammatory diseases

Design, Synthesis, and Structure–Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis

Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 264.7 macrophages. A majority of these derivatives effectively inhibited lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Preliminary structure–activity relationship analysis was also conducted. The results indicate that the most promising compounds in the prepared series were <b>14f</b> and <b>14g</b>. They were found to effectively reduce LPS-induced pulmonary inflammation and overexpression of a series of inflammatory mediators. Furthermore, in vivo administration of <b>14f</b> and <b>14g</b> resulted in remarkable lung histopathological improvements in mice without toxicity in organs. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful for further treatment in inflammatory diseases