SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.

Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.

E Platinum, a newly synthesized platinum compound, induces autophagy via inhibiting phosphorylation of mTOR in gastric carcinoma BGC-823 cells.

A tightly regulated catabolic process named autophagy involves the degradation of intracellular components via lysosomes. Here we investigate the antitumor effect of E Platinum, a newly synthesized derivative of oxaliplatin, in vivo and in vitro. E Platinum exhibits growth inhibition of various tumor cells in a dose-dependent manner, but the mechanism underlying it is unclear. Based on theory introducing autophagy, we preliminarily investigate whether autophagy could contribute to the antitumor activity of E Platinum. Our results showed that autophagy induced by 12.5 µM E Platinum in gastric carcinoma BGC-823 cells was significantly characterized by the FITC-fluorescent microtubule associated protein 1 light chain 3 (MAP-LC3), lysosomal-rich/acidic compartments visualized with Lysotracker red (LTR-red) and an accumulation of numerous large autophagic vesicles within the cytoplasm, but not in the control cells. Meanwhile treatment of cells with 12.5 µM E Platinum resulted in conversion of water soluble LC3 (LC3-I) to lipidated and autophagosome-associated form (LC3-II) as well as increasing expression of autophagy protein Beclin 1. Activation of predominant lysosomal aspartic protease, LAMP-1 and cathepsin D, was demonstrated. Moreover, RNA interference targeting Beclin 1, inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine significantly suppressed the above process as well as the BGC-823 cells growth inhibition triggered by 12.5 µM E Platinum. Studies of mechanism revealed that E Platinum suppressed activation of mTOR and p70S6K by decreasing phosphorylation of Akt, ERK1/2, JNK and p38 involved in mitogen-activated protein kinase signaling. We supported new evidences for E Platinum as a promising antitumor agent, involving with autophagy induction.

cis-1,2-Bis{[4-(4-pyrid-yl)pyrimidin-2-yl]sulfanylmeth-yl}benzene.

The mol-ecular skeleton of the title mol-ecule, C(26)H(20)N(6)S(2), adopts a cis conformation with the two arms positioned on one side of the benzene ring plane. Intra-molecular π-π inter-actions between the pyrimidine rings [centroid-centroid distance = 3.654 (2) Å] and between the pyridine rings [centroid-centroid distance = 3.775 (2) Å] help to set the mol-ecular conformation; the pyrimidine rings, as well as the pyridine rings, are nearly parallel, forming dihedral angles of 4.12 (14) and 2.46 (14)°, respectively.

A polymeric ladder complex: catena-poly[[[micro-4,4'-bipyridyl-bis[aqua(p-aminobenzoato)copper(II)]]-di-mu-4,4'-bipyridyl] dinitrate tetrahydrate].

The title polymeric ladder complex, [[Cu(2)(C(7)H(6)NO(2))(2)(C(10)H(8)N(2))(3)(H(2)O)(2)](NO(3))(2).4H(2)O](n), has been synthesized and spectroscopically characterized. The polymeric nature of the compound involves two non-equivalent 4,4'-bipyridyl ligands acting as almost orthogonal bridges joining the metal coordination Jahn-Teller-distorted octahedra, and forming ladders packed under the influence of hydrogen bonds involving the uncoordinated amino group of the p-aminobenzoate ligand, the NO(3)(-) anion and the water molecules.

(1R,3S)-1-Monoamidocamphoric acid.

The title compound, (1S,3R)-3-carbamoyl-2,2,3-trimethylcyclopentane-1-carboxylic acid, C(10)H(17)NO(3), was synthesized and characterized by IR, EA, ES-MS (electrospray ionization mass spectra), (1)H NMR, (13)C NMR and X-ray diffraction techniques. The two independent molecules form a two-dimensional network via O-H.O and N-H.O hydrogen-bonding interactions between their carboxylic acid and carbamoyl groups.