Designing Multi-Target Drugs
Chapter 14: Discovery of HDAC-Inhibiting Multi-Target Inhibitors
Published:28 Mar 2012
Special Collection: 2012 ebook collection , 2011-2015 industrial and pharmaceutical chemistry subject collectionSeries: Drug Discovery
Xiong Cai, Changgeng Qian, 2012. "Discovery of HDAC-Inhibiting Multi-Target Inhibitors", Designing Multi-Target Drugs, J. Richard Morphy, C John Harris
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Several HDAC-inhibiting multiple-target inhibitors have been reported. In this chapter, the current progress in investigating HDAC-inhibiting multi-target inhibitors is briefly reviewed, with a focus on the first and only clinical candidate CUDC-101 as the case study example. CUDC-101 is a novel small molecule potently inhibiting activities of the EGFR and HER2 kinases and HDAC enzymes with IC50 values of 2.4, 15.7, and 4.4nM, respectively. CUDC-101's rational design and synthesis, superior in vitro potency, broad anti-proliferative and pro-apoptotic activities in cultured tumor cells including RTK inhibitor-resistant cell lines, effective network disruption in survival signaling pathways, high efficacy in in vivo xenograft animal models, favorable safety profile, and preliminary evidence of anti-tumor activity in phase I trials are presented in this chapter. This case study provides proof-of-principle that a single molecule with multiple targeted specificities can improve the effectiveness of current anticancer therapeutics preclinically.