Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC50 values and achieved picomolar DC50 values and >99% of maximum degradation (Dmax) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-METY1230H and c-METD1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

Broad spectrum inhibitors of 3C and 3CL proteases:research advances / 国际药学研究杂志

Picornaviruses(PV)and coronaviruses(CoV) are positive-stranded RNA viruses. Pathogens in the family can cause hand,foot and mouth disease,myocarditis, common cold ,severe respiratory and intestinal diseases. 3C and 3CL proteases, belonging to cysteine proteases,are required to process polyproteins into mature proteins for viral replication,which plays an impor?tant role in viral replication because substrate binding sites are highly conservative and have similar catalytic mechanism. 3C and 3CL proteases are different from protease in the human body ,which represents a promising anti-viral drug target. Using 3C and 3CL pro?teinase structural similarities,broad spectrum protease inhibitors have been found successfully. This review describes recent develop?ments of broad spectrum protease inhibitors targeting on 3C and 3CL proteases,and briefly illustrates the mechanism of the inhibitors, which may benefit to the development of virus therapy.

Synthesis and evaluation of new 3-aminooxazolidin-2-one derivatives for inhibiting bacterial quorum sensing / 国际药学研究杂志

Objective To develop some 3-aminooxazolidin-2-one derivatives with bacteria quorum sensing(QS)inhibitory ac?tivity. Methods Using(2-hydroxyethyl)hydrazine as raw material,we finished the synthesis through cyclization,condensation,hy?drolysis and condensation reaction,and evaluated their inhibition of QS via Chromobacterium violaceum. Results Eight compounds were synthesized and their structures were confirmed by 1H NMR and MS characterization. Compounds Z2 had inhibitory effect against QS. Conclusion None of the eight synthesized compounds have been reported before and the synthetic route is reliable. Compounds Z2 have inhibitory effect against QS.

HPLC determination of metoclopramide and its related substances in metoclopramide nasal spray / 军事医学

Objective To establish an HPLC method for the determination of metoclopramide (MCP) and its related substances in MCP nasal spray .Methods Chromatographic separation was performed on an Agilent TC-C18 column (250 mm ×4.6 mm,5 μm) using acetonitrile and phosphate buffer solution (0.05 mol/L potassium dihydrogen phosphate solution, added with 5 ml of triethylamine and adjusted to pH 4.0 with phosphoric acid)(19∶81) as the mobile phase at 1.0 ml/min.The detection wavelength was 275 nm and the column temperature was set at 30℃.Results and Conclusion Related substances were completely separated from MCP .For MCP,the linearity of determination was over the range of 10-200 μg/ml and the recovery of the method ranged from 100.3%to 101.6%.The relative standard deviation was 0.68%(n=9).The method is accurate, reliable, repeatable, and could be readily utilized as a quality control method for MSP nasal spray .

Screening of chemokine receptor CCR4 antagonists by capillary zone electrophoresis / 药物分析学报

CC chemokine receptor 4 (CCR4) is a kind of G-protein-coupled receptor, which plays a pivotal role in allergic inflammation. The interaction between 2-(2-(4-chloro-phenyl)-5-{[(naphthalen-1-ylmethyl)-carbamoyl]-methyl}-4-oxo-thiazolidin-3-yl)-N-(3-morpholin-4-yl-propyl)-acetamide (S009) and the N-terminal extracellular tail (ML40) of CCR4 has been validated to be high affinity by capillary zone electrophoresis (CZE). The S009 is a known CCR4 antagonist. Now, a series of new thiourea derivatives have been synthesized. Compared with positive control S009, they were screened using ML40 as target by CZE to find some new drugs for allergic inflammation diseases. The synthesized compounds XJH-5, XJH-4, XJH-17 and XJH-1 displayed the interaction with ML40, but XJH-9, XJH-10, XJH-11, XJH-12, XJH-13, XJH-14, XJH-3, XJH-8, XJH-6, XJH-7, XJH-15, XJH-16 and XJH-2 did not bind to ML40.Both qualification and quantification characterizations of the binding were determined. The affinity of the four compounds was valued by the binding constant, which was similar with the results of chemotactic experiments. The established CEZ method is capable of sensitive and fast screening for a series of lactam analogs in the drug discovery for allergic inflammation diseases.

Establishment of a cell-based 2009 H1N1 influenza neuraminidase inhibitors evaluation system / 药学学报

This study is to establish a cell-based model targeting to neuraminidase (NA) of the 2009 H1N1 influenza A virus. NA is an influenza virus structural protein with enzymatic activity of the cleavage of HA-sialic acid interaction to release new viral particles from cells. A model of HIV-1 (pNL4-3.Luc.R(-)E(-)) based pseudovirions packed with HA [hemagglutinin, A/VietNam/1203/2004 (H5N1)] and NA [A/California/04/2009 (H1N1)] was established to evaluate compounds activities on NA function. The viral release can be blocked by neuraminidase inhibitors, oseltamivir and oseltamivir carboxylate, with IC50 of (61 +/- 31) nmol L(-1) and (5.5 +/- 2.9) nmol L(-1) respectively. A point mutation of H275Y on NA leads oseltamivir-resistance. This corresponding mutation was introduced into the system which was also confirmed by oseltamivir and oseltamivir carboxylate.