DDX3, a potential target for cancer treatment

Abstract

RNA helicases are a large family of proteins with a distinct motif, referred to as the DEAD/H (Asp-Glu-Ala-Asp/His). The exact functions of all the human DEAD/H box proteins are unknown. However, it has been consistently demonstrated that these proteins are associated with several aspects of energy-dependent RNA metabolism, including translation, ribosome biogenesis, and pre-mRNA splicing. In addition, DEAD/H box proteins participate in nuclear-cytoplasmic transport and organellar gene expression.A member of this RNA helicase family, DDX3, has been identified in a variety of cellular biogenesis processes, including cell-cycle regulation, cellular differentiation, cell survival, and apoptosis. In cancer, DDX3 expression has been evaluated in patient samples of breast, lung, colon, oral, and liver cancer. Both tumor suppressor and oncogenic functions have been attributed to DDX3 and are discussed in this review. In general, there is concordance with in vitro evidence to support the hypothesis that DDX3 is associated with an aggressive phenotype in human malignancies. Interestingly, very few cancer types harbor mutations in DDX3, which result in altered protein function rather than a loss of function.Efficacy of drugs to curtail cancer growth is hindered by adaptive responses that promote drug resistance, eventually leading to treatment failure. One way to circumvent development of resistant disease is to develop novel drugs that target over-expressed proteins involved in this adaptive response. Moreover, if the target gene is developmentally regulated, there is less of a possibility to abruptly accumulate mutations leading to drug resistance. In this regard, DDX3 could be a druggable target for cancer treatment. We present an overview of DDX3 biology and the currently available DDX3 inhibitors for cancer treatment.

Fig. 1

Phylogenetic tree depicting homologous of DDX3. a. Phylogram of human DDX3 homologous (Ded1/P68 cluster) made in clustalX (guide tree). b. Phylogram of DDX3 orthologs in commonly used model organisms made in clustalX (guide tree)

Fig. 2

Structure of RNA helicase DDX3. a. Schematic representation of DDX3 (human) and conserved motifs. In grey the two RecA-like domains. The motifs include Q (¹⁸²F--²⁰⁰YTRPTPVQ), I (²²⁶TGSGKT), Ia (²⁷⁴PTRELA), Ib (³⁰²GG), Ic (³²³TPGR), II (³⁴⁷DEAD), III (³⁸²SAT), IV (⁴⁴⁵LVFVET), Iva (⁴⁷⁷QRDR--⁴⁸⁷F), V (⁴⁹⁴ILVAT), Va (⁵⁰²ARGLD), VI (⁵²⁷HRIGRTGR). Conserved amino acid sequences are indicated in parenthesis. Boxes represent the conserved motifs involved in ATP binding (red), RNA binding (green) and linking (blue). b. Crystallography structure of DDX3 (V168-G582) (PDB: 2I4I) with AMP as the substrate (12 conserved motifs are indicated with colors)

Fig. 3

DDX3 interactions with AMP. a. Hydrogen interactions between AMP and amino acid residues of DDX3 ATP binding pocket: the C6 amino group of AMP as a hydrogen donor (HD) and the backbone carbonyl oxygen of Arg202 as a hydrogen acceptor (HA); the 2’-OH group as well as N9 of AMP (both act as HA) and the phenolic oxygen of Tyr200 (HD); N7 of AMP (HA) and the side chain NH2 group of Gln207 (HD); two phosphate oxygens of AMP (HA) and the backbone NH groups of Gly229 and Thr 231 (HD). b. π-π interaction between the aromatic ring of AMP and the phenol side chain of Tyr200

Fig. 4

Structure of ring-expanded nucleosides targeting DDX3, REN-1 and REN-2 [96]

Fig. 5

Inhibitors of DDX3 helicase function

Fig. 6

DDX3 inhibitor RK-33. a. Structure of 5:7:5 tricyclic heterocycle RK-33. b. Graphic depiction of the interaction of DDX3 and RK-33 and the subsequent biological effect