Chapter 14: Discovery of HDAC-Inhibiting Multi-Target Inhibitors

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.