Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells

Abstract

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.

A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells

“…Human primary epithelial gingival keratinocytes (HPK), and normal colon fibroblast CRL1459 cells were purchased from American Type Culture Collection (ATCC#PCS-200-014, and ATCC#CCD-18Co—CRL-1459, respectively, Manassas, VA, USA). These cells were grown as an adherent monolayer with Dulbecco’s Modified Eagle’s Medium (Corning, Tewksbury, MA, USA) supplemented with 10% fetal bovine serum (Biofluids Technologies, Port Richey, FL, USA), 2 mM of L-glutamine and 100 U/mL of penicillin and 100 µg/mL of streptomycin (Thermo Fisher Scientific, Inc., Waltham, MA, USA), as previously described [ 42 ]. HPKs cells were cultured in dermal cell basal medium (ATCC# PCS-200-030) supplemented with factors from Keratinocyte growth kit (ATCC# PCS-200-040) as per manufacture’s protocol.…”

Antithrombotic and antiplatelet activity of an organometallic rhodium(I) complex incorporating a substituted thieno‐[2,3‐d]‐pyrimidine ligand: Synthesis, structural characterization, and molecular docking calculations

“…Methyl 2-amino-4-(diethylamino)-thieno-[2,3-d]-pyrimidine-6-carboxylate, abbreviated as tpc within the text, has been selectively chosen in order to rationally design a neutral complex containing the cod hydrophobic moiety on the metal core. This organic compound (tpc) belongs to the class of thieno- [2,3-d]pyrimidines that displays interesting biological abilities, [24] such as anticancer, [25,26] analgesic, [27] antimicrobial, [28] kinase receptor inhibitors, [29] and anti-inflammatory. [30] Therefore, in order to achieve the above mentioned goals, we set out to synthesize a model compound, target molecule (prototype), so as to collect preliminary results about its action against PAF-induced aggregation both in WRPs and in human platelets.…”

Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation

“…The flipped anionic PS binds to the Ca 2+ -dependent phospholipid-binding protein, annexin V [ 49 ]. We discovered and reported several potent apoptosis-inducing compounds [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. In this study, the result of our morphological studies in MDA-MB-231 cells after incubation with our lead compounds, 4g and 4i, indicated that apoptosis was occurring ( Figure 3 A).…”