RESUMEN
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).
RESUMEN
A series of 5H-benzo[b] carbazole derivatives were synthesized to find new TopⅡ inhibitors.The substitution pattern at C-9 was discussed.All 16 compounds were tested for their antiproliferative activities against 4 tumor cell lines (SMMC-7721,S1,HCT116,and HeLa) by sulforhodamine B assay.Four compounds were found to inhibit the proliferation of all tested cell lines.And compound 10e displayed the best antiproliferative activity against all 4 tested cell lines with IC50 values of 5.06,4.50,5.29,and 6.32 μmol/L,respectively.
RESUMEN
@#Type 2 diabetes, an epidemic disorder characterized by high blood glucose level associated with microvascular complications, is one of the main causes of human suffer across the globe, with no effective medicine up to now. AMP-activated protein kinase(AMPK), a highly conserved serine/threonine protein kinase, is a key sensor and regulator of intracellular and whole-body energy metabolism. Small molecule AMPK direct activators have been proven to lower blood-glucose, which is a promising candidate for the treatment of type 2 diabetes. The progress on the research of small molecule AMPK direct activators in recent years is summarized in this paper.