Design and synthesis of 4th generation EGFR inhibitors against human triple (Del19/T790M/C797S) mutation.

Epidermal growth factor receptor (EGFR)-targeted therapy is used to treat EGFR mutation-induced non-small cell lung cancer (NSCLC). However, its efficacy does not last beyond a certain period due to the development of primary and secondary resistance. First and second-generation inhibitors (e.g., gefitinib, erlotinib, and afatinib) induce EGFR T790M mutations, while third-generation inhibitors (e.g., osimertinib) induce C797S as a major target resistance mutation. Therefore, the C797S mutation is being actively researched. In this study, we investigated the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against the C797S mutation. We identified a compound 13k that displayed nanomolar potency and high selectivity. Moreover, we used a triple mutant xenograft mouse model to evaluate the in vivo efficacy of 13k in inhibiting EGFR C797S, which demonstrated exceptional profiles and satisfactory EGFR C797S inhibition efficacy. Based on its excellent in vitro and in vivo profiles, compound 13k can be considered a promising candidate for treating EGFR C797S mutations.

Surface ultrastructure and mechanical properties of three different white-coated NiTi archwires.

The recent trend in orthodontic treatment is to apply esthetic materials to orthodontic appliances with adequate clinical performance. The aim of this study was to investigate the ultrastructure (surface roughness) and mechanical properties (load-deflection curve) of three as-received, white-coated superelastic nickel-titanium (NiTi) archwires using atomic force microscopy (AFM) and modified three-point bending test assessments, respectively. Three representative esthetic NiTi archwires were used, silver-platinum- and polymer-coated NiTi Natural Dany (Dany group), epoxy resin-coated Orthoforce Ultraesthetic™ (Ultra group), and Teflon®-coated Perfect (Perfect group). Uncoated metallic areas of each wire were used as controls. The diameter of the Perfect archwire was significantly larger than that of other archwires. The Dany and Ultra groups showed more deflection than the Perfect group. The hysteresis area of the Dany and Ultra groups showed approximately two- and fourfold increases compared to the control and the Perfect group. The Dany group (2037.5 ± 527.3 nm) had the highest peak-to-peak surface roughness in the coated areas, followed by the Ultra group (811.1 ± 407.5 nm) and the Perfect group (362.7 ± 195.8 nm). However, reverse nanostructural changes in the surface roughness were observed in the uncoated metallic areas. The results suggested that the load-deflection properties and the surface roughness of superelastic NiTi archwires were affected directly by the coating materials. Although the efficiency of orthodontic treatment was affected by various factors, when only considering the frictional force and mechanostructural properties, the epoxy resin-coated Orthoforce Ultraesthetic™ archwires were the most effective for orthodontic treatment.

2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3-ylmethyl) C-region.

A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K(i(CAP)) = 0.2 nM; IC(50(pH)) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.