Hongbing Zhao

Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity

A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line. Several compounds showed potent inhibition with an IC(50) value less than 0.10 microM. Structure-activity relationships for this class of compounds at the 2- and 5-position of the pyrimidine scaffold have been elucidated. The most active compound 7gc showed good inhibition of several different human cancer cell lines with IC(50) values from 0.024 to 0.55 microM.

YHHU0895, a novel synthetic small-molecule microtubule-destabilizing agent, effectively overcomes P-glycoprotein-mediated tumor multidrug resistance

P-glycoprotein-mediated multidrug resistance (MDR) is a major limiting factor in the efficacy of most microtubule-targeting agents. Here, we investigated the novel, synthetic, and small-molecule microtubule-destabilizing agent, 2-(2-amino-5-(1-ethyl-1H-indol-5-yl) pyrimidin-4-yl) phenol (YHHU0895), for its anti-tumor activity and potential for overcoming P-glycoprotein-mediated MDR. YHHU0895 inhibited purified tubulin polymerization through binding to tubulin at the colchicine-binding site and significantly inhibited human tumor cell proliferation. Notably, P-glycoprotein-overexpressing KBV200 and K562/ADR cells, which are strongly resistant to colchicine, vinorelbine and paclitaxel, were sensitive to YHHU0895 both in vitro and in vivo. These findings indicate that YHHU0895 is a novel type of microtubule-destabilizing agent that has the potential for the treatment of patients with drug resistance mediated by P-glycoprotein.

A novel and simple hollow-fiber assay for in vivo evaluation of nonpeptidyl thrombopoietin receptor agonists

Preclinical in vivo assessment of the pharmacologic activity of nonpeptidyl thrombopoietin receptor (TPOR) agonists is very difficult because of the high species specificity of such agonists. In this study, we have developed a novel and simple in vivo hollow-fiber assay to preclinically evaluate TPOR agonists. The 32D-mpl cell line was generated by stable transfection of human TPOR into 32D lymphoblast cells and shown to be a specific model for nonpeptide TPOR agonists in vitro. Stably transfected 32D-mpl cells were then sealed in hollow fibers and implanted into nude mice. Cells in hollow fibers specifically responded to TPOR agonists, including thrombopoietin and eltrombopag, a nonpeptide small-molecule TPOR agonist, but not to granulocyte colony-stimulating factor or erythropoietin. Oral administration of eltrombopag stimulated 32D-mpl cell proliferation, prevented 32D-mpl cell apoptosis, and stimulated the phosphorylation of cellular signaling transducers and activators of transcription in a TPOR- and dose-dependent manner. These results indicate that the hollow-fiber assay is a specific and efficient model for rapidly evaluating the in vivo activity of small-molecule TPOR agonists.

Abstract 3604: Preclinical antitumor study of famitinib, an orally available multi-targeted kinase inhibitor of VEGFR/PDGFR/c-Kit in phase I clinical trials

Angiogenesis plays a key role in tumor progression and anti-angiogenic agents including sunitinib and sorafenib that target VEGF/VEGFR signaling pathway have been proved to an effective therapy for cancer in the clinic. However, severe side effects such as hypertension and bone marrow toxicity limit their clinical application. Thus, development of novel anti-angiogenic agents with fewer side effects is still an unmet challenge. In this study, we characterized the in vitro and in vivo antitumor activity of famitinib, an orally active multi-targeted kinase inhibitor. Famitinib inhibited the activity of c-kit, VEGFR-2, PDGFRα and PDGFRβ with IC50 values of 2.3 nM, 4.7 nM and 6.6 nM, respectively. In addition, Famitinib inhibited the VEGF-induced proliferation, migration and tubule formation of human umbilical vein endothelial cells, and micro-vessel spouting from matrigel-embedded rat aortic rings. In vivo, famitinib exhibited broad and potent anti-tumor activity, leading to regression or growth arrest of various established xenografts derived from human tumor cell lines. Moreover, famitinib significantly enhanced the efficacy of oxaliplatin or 5-fluorouracil when they were combined. In summary, famitinib has potent preclinical antitumor activity which supports its further evaluation in clinic. Famitinib is currently in phase I clinical trials in China. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3604. doi:10.1158/1538-7445.AM2011-3604