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The FOXM1 protein controls the expression of essential genes related to cancer cell cycle progression, metastasis, and chemoresistance. We hypothesize that FOXM1 inhibitors could represent a novel approach to develop 18 F-based radiotracers for Positron Emission Tomography (PET). Therefore, in this report we describe the first attempt to use 18 F-labeled FOXM1 inhibitors to detect triple-negative breast cancer (TNBC). Briefly, we replaced the original amide group in the parent drug FDI-6 for a ketone group in the novel AF-FDI molecule, to carry out an aromatic nucleophilic ( 18 F)-fluorination. AF-FDI dissociated the FOXM1-DNA complex, decreased FOXM1 levels, and inhibited cell proliferation in a TNBC cell line (MDA-MB-231). [ 18 F]AF-FDI was internalized in MDA-MB-231 cells. Cell uptake inhibition experiments showed that AF-FDI and FDI-6 significantly decreased the maximum uptake of [ 18 F]AF-FDI, suggesting specificity towards FOXM1. [ 18 F]AF-FDI reached a tumor uptake of SUV=0.31 in MDA-MB-231 tumor-bearing mice and was metabolically stable 60 min post-injection. These results provide preliminary evidence supporting the potential role of FOXM1 to develop PET radiotracers., (© 2021 Wiley-VCH GmbH.)

Autotaxin (ATX) is a secreted enzyme responsible for producing lysophosphatidic acid (LPA). The ATX/LPA signaling axis is typically activated in wound healing and tissue repair processes. The ATX/LPA axis is highjacked and upregulated in the progression and persistence of several chronic inflammatory diseases, including cancer. As ATX inhibitors are now progressing to clinical testing, innovative diagnostic tools such as positron emission tomography (PET) are needed to measure ATX expression in vivo accurately. The radiotracer, [ 18 F]PRIMATX, was recently developed and tested for PET imaging of ATX in vivo in a murine melanoma model. The goal of the present work was to further validate [ 18 F]PRIMATX as a PET imaging agent by analyzing its in vivo metabolic stability and suitability for PET imaging of ATX in models of human 8305C thyroid tumor and murine 4T1 breast cancer. [ 18 F]PRIMATX displayed favorable metabolic stability in vivo (65% of intact radiotracer after 60 min p.i.) and provided sufficient tumor uptake profiles in both tumor models. Radiotracer uptake could be blocked by 8-12% in 8305C thyroid tumors in the presence of ATX inhibitor AE-32-NZ70 as determined by PET and ex vivo biodistribution analyses. [ 18 F]PRIMATX also showed high brain uptake, which was reduced by 50% through the administration of ATX inhibitor AE-32-NZ70. [ 18 F]PRIMATX is a suitable radiotracer for PET imaging of ATX in the brain and peripheral tumor tissues.

A new series of 1,3,5-trisubstituted 2-pyrazolines for the inhibition of cyclooxygenase-2 (COX-2) were synthesized. The designed structures include a COX-2 pharmacophore SO 2 CH 3 at the para-position of the phenyl ring located at C-5 of a pyrazoline scaffold. The synthesized compounds were tested for in vitro COX-1/COX-2 inhibition and cell toxicity against human colorectal adenocarcinoma cell lines HT-29. The lead compound (4-chlorophenyl){5-[4-(methanesulfonyl)phenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}methanone (16) showed significant COX-2 inhibition (IC 50 =0.05±0.01 μM), and antiproliferative activity (IC 50 =5.46±4.71 μM). Molecular docking studies showed that new pyrazoline-based compounds interact via multiple hydrophobic and hydrogen-bond interactions with key binding site residues of the COX-2 enzyme., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Human polo-like kinase 1 (Plk1) is involved in cell proliferation and overexpressed in a broad variety of different cancer types. Due to its crucial role in cancerogenesis Plk1 is a potential target for diagnostic and therapeutic applications. Peptidic ligands can specifically interact with the polo-box domain (PBD) of Plk1, a C-terminal located phosphoepitope binding motif. Recently, phosphopeptide MQSpTPL has been identified as ligand with high binding affinity. However, a radiolabeled version of this peptide showed only insufficient cellular uptake. The present study investigated peptide dimers consisting of PBD-targeting phosphopeptide MQSpTPL and a cell-penetrating peptide (CPP) moiety. The new constructs demonstrate superior uptake in different cancer cell-lines compared to the phosphopeptide alone. Furthermore, we could demonstrate binding of phosphopeptide-CPP dimers to PBD of Plk1 making the compounds interesting leads for the development of molecular probes for imaging Plk1 in cancer., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cyclin-dependent kinases 4 and 6 (Cdk4/6) are important components of cell cycle activation and control in early G(1) phase. Both enzymes and their regulators, e.g., cyclins, play critical roles in embryogenesis, homeostasis, and cancerogenesis. Cdk4/6 are attractive targets for cancer treatment. Recently, numerous selective small molecule inhibitors of Cdk4/6 have been developed. The potential of Cdk4/6 inhibitors, particularly, pyrido[2,3-d]pyrimidine derivatives, as both anti-cancer drugs and 124I- and 18F-radiolabeled tracers for cancer imaging using positron emission tomography is discussed.

The cyclin-dependent kinase (Cdk)-cyclin D/retinoblastoma (pRb)/E2F cascade, which controls the G1/S transition of cell cycle, has been found to be altered in many neoplasias. Inhibition of this pathway by using, for example, selective Cdk4 inhibitors has been suggested to be a promising approach for cancer therapy. We hypothesized that appropriately radiolabeled Cdk4 inhibitors are suitable probes for tumor imaging and may be helpful studying cell proliferation processes in vivo by positron emission tomography. Herein, we report the synthesis and biological, biochemical, and radiopharmacological characterizations of two 124I-labeled small molecule Cdk4 inhibitors (8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]-pyrimidin-7-one (CKIA) and 8-cyclopentyl-6-iodo-5-methyl-2-(5-(piperazin-1-yl)-pyridin-2- yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one (CKIB)). Our data demonstrate a defined and specific inhibition of tumor cell proliferation through CKIA and CKIB by inhibition of the Cdk4/pRb/E2F pathway emphasizing potential therapeutic benefit of CKIA and CKIB. Furthermore, radiopharmacological properties of [124I]CKIA and [124I]CKIB observed in human tumor cells are promising prerequisites for in vivo biodistribution and imaging studies. [ABSTRACT FROM AUTHOR]

• Novel series of 1,5-disubstituted tetrazoles were designed and synthesized. • In vitro bioassay data of the novel azoles as COX-1/COX-2 inhibitors were shown. • In vitro antiproliferative data were described. • Selected probes were docked in COX-1, COX-2, and bcr/abl kinase enzymes. • The structural modifications improved the biological activities of the new probes. A unique class of 1,5-disubstituted tetrazoles was designed and synthesized, and their biological activities as cyclooxygenase (COX) inhibitors and anti-cancer agents were determined experimentally and assessed with molecular docking studies for two isoenzymes COX-1 and COX-2, as well as oncogenic tyrosine kinase bcr/abl enzymes. The structural modifications of this study comprised five different substitutions at the hydroxy group of our model compound 1. All new compounds showed an enhanced inhibition potency toward COX-2 enzyme with no significant inhibition toward COX-1 enzyme. Tetrazole 4 showed not only the highest desirable inhibition potency for both COX-2 enzyme (IC 50 = 0.086 µM,) and COX-1 isoenzyme (IC 50 = 61 µM), but also the best selectivity for COX-2 enzyme (SI = 714). Azoles 2, 3 , and 5 showed a moderate activity against the human breast cancer cell line (MCF-7; IC 50 = 40.68 µM, 70.71 µM, and 13.52 µM, respectively), while among the studied compounds only azole 5 showed anti-cancer activity against the human immortalized myelogenous leukemia (K562), (IC 50 = 26.88 µM). All investigated compounds displayed no cytotoxicity for the HDFa (Human Dermal Fibroblasts Adult) cell lines (IC 50 = >100 µM). [Display omitted] [ABSTRACT FROM AUTHOR]