RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

Abstract

Introduction: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.

RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier

“…Since hypermethylation of TSGs is cell line dependent we chose A549 cells to study the effect of RX-3117 on protein expression of O-6-methylguanine-DNA methyltransferase (MGMT) and E-cadherin, while SW1573 cells were chosen to study the effect on p16. Earlier we demonstrated a concentration and time-dependent down-regulation of DNMT1 in cell lines with various histological backgrounds (NSCLC, ovarian cancer, pancreatic cancer, breast cancer) [1,3,4].…”

“…RX-3117 is a novel cytidine analog modified in the sugar ring moiety [1] (Figure 1), which has shown promising anti-tumor activity against gemcitabine resistant xenografts from different pathologies [2] and is currently in clinical trial (NCT02030067) [3]. RX-3117 was shown to down-regulate DNA methyl transferase 1 (DNMT1) [1,[3][4][5][6]. The pharmacological consequences of this inhibition, however, have not been identified.…”

Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogues

“…Finally, global deprotection was achieved by sequential treatment with methanolic ammonia and BBr 3 , providing uracil derivate 85 which was converted to 76 via a standard four-step process. Of the four nucleoside analogues evaluated (Figure 8), derivative 76 showed significant potency against several human cancer cell lines (Table 3) [51,54,55]. Furthermore, Jeong reported that 76 also showed significant antitumour activity in a nude mouse xenograft model implanted with A549 human lung cancer cells, wherein after 38 days the inhibition of tumour growth was 32% and 58% at 3 and 10 mg/kg doses, respectively [54].…”

DNA Methylation as a Therapeutic Target for Bladder Cancer

“…RX-3117 (fluorocyclopentenylcytosine) is a novel cytidine analogue with a modified ribose molecule [ 89 ]. To be incorporated into DNA or RNA, the RX-3117 molecule is firstly activated through transformation into a triphosphate form by uridine–cytidine kinase 2 [ 90 ]. Although RX-3117 is not a substrate for cytidine deaminase [ 89 ], other enzymes such as NT5C3 may have a role in breaking an intermediate monophosphate form, resulting in RX-3117 inactivation [ 90 ].…”

“…To be incorporated into DNA or RNA, the RX-3117 molecule is firstly activated through transformation into a triphosphate form by uridine–cytidine kinase 2 [ 90 ]. Although RX-3117 is not a substrate for cytidine deaminase [ 89 ], other enzymes such as NT5C3 may have a role in breaking an intermediate monophosphate form, resulting in RX-3117 inactivation [ 90 ]. RX-3117′s anti-tumor effects were evaluated in nine different xenograft mouse models and showed promise for the treatment of tumors that are sensitive and resistant to gemcitabine [ 91 ].…”