The overall objective is to develop potent anti-CXCR4 drugs that are specific and safe. Even though CXCR4 is a good target for intervening various diseases, especially, cancer metastasis, there is no safe drug in the clinic until now. Metastasis is an end result for many solid tumor types and is the leading cause of cancer related deaths. This has attracted an increasing amount of attention from research groups over the last decade in both academia and industry, as a target for metastatic disease intervention and life extension. To date, a number of target molecules have been addressed that are linked mechanistically to the various sub- steps associated with metastasis including: i) establishment of angiogenesis at the primary site;ii) locomotion;iii) chemoattraction, homing, and adhesion of the metastatic cells to the defined organs;and iv) establishment of metastatic tumor growth and angiogenesis. The CXCR4/SDF-1 interaction, and the resulting cell signaling cascade, has recently emerged as one of the most relevant such targets as it has been shown to play a key role in all four steps outlined above. A set of small molecule CXCR4 antagonists has been discovered and we are currently in the process of evaluating specificity and potency. We are simultaneously designing and generating new analogs to optimize efficacy as well as expand our structural scope. WZ40 is currently the most advanced, which potently bind to CXCR4, thus, blocking the CXCR4/SDF-1 signaling process. We have followed this discovery by demonstrating that WZ40 inhibits tumor metastasis by inhibiting the CXCR4/SDF-1 interaction in both in vitro and in vivo studies. Our underlying hypothesis is that WZ40 and its analogs are specific inhibitors of CXCR4/SDF-1 interaction.
The specific aims are: 1. Design and prepare improved inhibitors with increasingly diverse chemical scaffolds;2. Determine the Specificity of selected compounds against other chemokine receptors;and 3. Select and progress suitable candidates based on plasma stability, oral availability, and in vivo efficacy. The intended outcome of this proposal is the identification of small molecules that will attenuate tumor metastasis in vivo by blocking CXCR4 function whilst demonstrating a sufficient pharmacokinetic and specificity profile to merit advancement into human clinical evaluation.
|Yoon, Younghyoun; Mohs, Aaron M; Mancini, Michael C et al. (2016) Combination of an Integrin-Targeting NIR Tracer and an Ultrasensitive Spectroscopic Device for Intraoperative Detection of Head and Neck Tumor Margins and Metastatic Lymph Nodes. Tomography 2:215-222|
|Bai, Renren; Liang, Zhongxing; Yoon, Younghyoun et al. (2016) Symmetrical bis-tertiary amines as novel CXCR4 inhibitors. Eur J Med Chem 118:340-50|
|Liang, Zhongxing; Ahn, Jeffrey; Guo, Donna et al. (2013) MicroRNA-302 replacement therapy sensitizes breast cancer cells to ionizing radiation. Pharm Res 30:1008-16|
|Olivera, Anlys; Moore, Terry W; Hu, Fang et al. (2012) Inhibition of the NF-?B signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol 12:368-77|
|Wei, Li; Hong, Samuel; Yoon, Younghyoun et al. (2012) Early prediction of response to Vorinostat in an orthotopic rat glioma model. NMR Biomed 25:1104-11|
|Liang, Zhongxing; Cho, Heidi T; Williams, Larry et al. (2011) Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer Progression. Nucl Med Mol Imaging 45:93-102|
|Liang, Zhongxing; Li, Yuhua; Huang, Ke et al. (2011) Regulation of miR-19 to breast cancer chemoresistance through targeting PTEN. Pharm Res 28:3091-100|
|Liang, Zhongxing; Wu, Hui; Xia, James et al. (2010) Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol 79:817-24|
|Zhu, Aizhi; Zhan, Weiqiang; Liang, Zhongxing et al. (2010) Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity. J Med Chem 53:8556-68|
|Shim, Hyunsuk; Oishi, Shinya; Fujii, Nobutaka (2009) Chemokine receptor CXCR4 as a therapeutic target for neuroectodermal tumors. Semin Cancer Biol 19:123-34|
Showing the most recent 10 out of 14 publications