Notes Bull. Korean Chem. Soc. 2013, Vol. 34, No. 12 3885 http://dx.doi.org/10.5012/bkcs.2013.34.12.3885 Identification of Potent Inhibitors against Human Peptide Deformylase as Anticancer Agents Sang Jae Lee, †,‡ Ok Sung Jung, § Bong-Jin Lee, ‡ Kwang-Hwi Cho, §,* and Byung Il Lee †,* † Research Institute, National Cancer Center, Goyang, Gyeonggi 410-769, Korea. * E-mail: bilee@ncc.re.kr ‡ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea § School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Korea. * E-mail: chokh@ssu.ac.kr Received August 30, 2013, Accepted September 16, 2013 Key Words : Anticancer agent, Inhibitor, Drug design, Peptide deformylase Peptide deformylase (PDF) catalyzes the removal of a formyl group from the N-terminal methionine residue of newly synthesized polypeptides in order to yield mature proteins. This deformylation step is an essential process in bacteria. 1,2 For this reason, PDF has been proposed as an attractive antibacterial target. 3,4 While it has been thought that only prokaryote PDFs are functional, recent studies have shown that eukaryotic PDFs, including human mito- chondrial PDF, are also active in vitro and in vivo. 5 The functionality of human PDF in human mitochondria strongly raises the possibility as a new cancer drug target. Moreover, the PDF inhibitors have been reported that they stimulate cell death or proliferation arrest in a variety of cancer cell lines. 5,6,7 Furthermore, inhibitors against PDF showed low toxicity to human and other animal cells. 8,9 Interestingly, it has been reported that the representative PDF inhibitor including actinonin has a considerable influence on innate immune reactions in human. 10,11 Such consequences can be beneficial for human and also serve to resist cancer. 11 Several inhibitory mechanism of PDF inhibitors against cancers has been suggested. 12 The PDF inhibitors may induce a tumor-specific mitochondrial membrane depolarization and ATP depletion, which promote cell death or arrest prolife- ration in a wide variety of cancer cell lines. 5-7 However, the exact mechanism of anticancer effect of PDF inhibitors is still unclear. In the present study, we aim to identify the new potent human PDF inhibitors for the development of anticancer reagents focused on breast cancer. These inhibitors were pre- viously reported to show strong inhibitory activities against pathogenic bacteria. 13 For the study, we tested two classes of PDF inhibitors, which consist of the hydroxamate/peptidomimetic [PMT387 (7a) and PMT497] and the reverse hydroxamate/nonpeptide scaffold inhibitors [PMT1039 (15e) and PMT1067] (Figure 1). Most known PDF inhibitors were developed based on the naturally occurring inhibitor, actinonin, which is composed of hydroxamate moiety and peptide backbone. The compound possessing hydroxamte moiety such as actinonin is an effective inhibitor, however, it shows poor selectivity by chelating the metals of other metalloproteins. This kind of compound can be cytotoxic to mammalian cells and presents poor oral bioavailability related to characteri- stic rapid metabolization. 14-16 Therefore, our newly develop- ed reverse hydroxamate/nonpeptide scaffold can aid in the design of new potential inhibitors against human PDF. In a biochemical enzyme assay, the Ki values for the four compounds [PMT387 (7a), PMT497, PMT1039 (15e), and PMT1067] inhibiting the human PDF were measured as 243.5(± 3.2), 91.3(± 29.5), 360.3(± 54.5), and 62.9(± 8.2) Figure 1. Chemical structures of the peptide-scaffold hydroxamate inhibitors [PMT387 (7a) and PMT497] and non-peptide scaffold reverse hydroxamate inhibitors [PMT1039 (15e) and PMT1067].