A5051084648- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Cancer-related Molecular Pathways
- Cancer therapeutics and mechanisms
- Radiopharmaceutical Chemistry and Applications
- Microtubule and mitosis dynamics
- DNA Repair Mechanisms
- Advanced Breast Cancer Therapies
- Neuroblastoma Research and Treatments
- PARP inhibition in cancer therapy
- Cancer Cells and Metastasis
- Bioactive Compounds and Antitumor Agents
- Ocular Oncology and Treatments
- Cancer Treatment and Pharmacology
- Glioma Diagnosis and Treatment
- Synthesis and Reactivity of Heterocycles
- CAR-T cell therapy research
- Estrogen and related hormone effects
- Synthesis and biological activity
- Lung Cancer Treatments and Mutations
- Synthesis and Biological Evaluation
- Chronic Lymphocytic Leukemia Research
- Phosphodiesterase function and regulation
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
Nerviano Medical Sciences
2007-2023
University of L'Aquila
2010
Pfizer (Italy)
2004
Pharmac
2001
Abstract Cdc7 is an evolutionarily conserved kinase that regulates S phase by promoting replication origin activation. Down-regulation of small interfering RNA in a variety tumor cell lines causes abortive phase, leading to death either p53-independent apoptosis or aberrant mitosis. Unlike fork blockade, Cdc7-depleted cells do not elicit robust checkpoint response; thus, inhibitory signals preventing additional cycle progression are generated. In normal fibroblasts, however, p53-dependent...
Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential new anticancer agents. In a previous article we described the lead discovery process 3-aminopyrazole class inhibitors. The endpoint this was PNU-292137, compound endowed with in vivo antitumor activity mouse tumor xenograft model. We optimized improve some physicochemical properties, notably solubility and plasma protein binding. This optimization brought us...
Abstract Two small‐molecule–drug conjugates (SMDCs, 6 and 7 ) featuring lysosomally cleavable linkers (namely the Val–Ala Phe–Lys peptide sequences) were synthesized by conjugation of α v β 3 ‐integrin ligand cyclo [DKP–RGD]‐CH 2 NH ( to anticancer drug paclitaxel (PTX). A third [DKP–RGD]–PTX conjugate with a nonpeptide “uncleavable” linker 8 was also be tested as negative control. These three SMDCs able inhibit biotinylated vitronectin binding purified V receptor at nanomolar concentrations...
Cdc7 kinase promotes and regulates DNA replication in eukaryotic organisms. Multiple mechanisms modulating activity response to stress have been reported, supporting the opposing notions that either plays an active role under these conditions or, conversely, is a final target inactivated by checkpoint response. We developed new immnunological reagents study properties of human cells challenged with ribonucleotide reductase inhibitor hydroxyurea or topoisomerase II etoposide. show Cdc7·Dbf4...
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. inhibition through siRNA or prototype small molecules causes p53 independent apoptosis tumor cells while reversibly arresting cell cycle progression primary fibroblasts. This implies that could be considered potential target for anticancer therapy. We previously reported pyrrolopyridinones (e.g., 1) are potent and selective inhibitors kinase, with good cellular potency vitro ADME properties but...
Altered expression and activity of cyclin-dependent kinase (CDK) tropomyosin receptor (TRK) families are observed in a wide variety tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation TRKs instead linked cancer survival dissemination. Here, we show that novel small-molecule PHA-848125, potent dual inhibitor CDKs TRKs, possesses significant antitumor activity....
CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and associated with extramedullary diffusion, multidrug resistance poor prognosis. We describe the establishment characterisation a novel disseminated model AML (AML-NS8), generated by injection into mice leukaemic blasts freshly isolated from patient an aggressive CD56(+) monoblastic (M5a). The reproduced typical manifestations this leukaemia, including presence masses central nervous system involvement, original phenotype,...
Abstract Current treatment of chronic lymphocytic leukemia (CLL) patients often results in life-threatening immunosuppression. Furthermore, CLL is still an incurable disease due to the persistence residual leukemic cells. These may therefore benefit from immunotherapy approaches aimed at immunoreconstitution and/or elimination following chemotherapy. For these purposes, we designed a simple GMP-compliant protocol for ex vivo expansion normal T cells patients’ peripheral blood adoptive...
Background and Purpose Malignant gliomas, the most common primary brain tumours, are highly invasive neurologically destructive neoplasms with a very bad prognosis due to difficulty in removing mass completely by surgery limited activity of current therapeutic agents. PHA ‐848125 is multi‐kinase inhibitor broad anti‐tumour pre‐clinical studies good tolerability phase 1 studies, which could affect two main pathways involved glioma pathogenesis, G 1‐ S progression control pathway through...
We have recently reported a new class of CDK2/cyclin A inhibitors based on bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction small alkyl or cycloalkyl groups in position 6 this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided way generating compounds with improved biochemical cellular activity. Optimization physical properties pharmacokinetic profile led to compound which exhibited good...
Herein we report the first example of an isoDGR-drug conjugate (2), designed to release paclitaxel selectively within cancer cells expressing integrin α
Theranostic RGD-camptothecin conjugates, possessing a disulfide linker and fluorescent naphthalimide moiety, were synthesized biologically evaluated. The conjugates showed nanomolar affinity for the purified αVβ3-integrin receptor. For antiproliferative assays, U87 human glioblastoma chosen as αVβ3-expressing cells, whereas non clone (U87 β3-KO) was generated negative control. Although β3-KO cells treated with statistically significant reduced fluorescence intensity (in range 7–12 %)...
Abstract The introduction of a hydrophobic group at position 7 9‐fluorenone‐2‐carboxylic acid generates new tubulin binders, the design which is suggested by modeling studies. synthesis based on use 2,7‐dibromo‐fluorenone as starting material. antiproliferative activity two different cell lines, fluorescent microscopy, flow cytometry, and sedimentation assay tests confirmed supposed mechanism.
New antibodies-drug conjugate (ADC) payloads overcoming chemoresistance and killing also poorly proliferating tumors at well-tolerated doses are much desired. Duocarmycins a well-known class of highly potent cytotoxic agents, with DNA minor groove-binding alkylation properties, active in chemoresistant tumors. Although different duocarmycin derivatives have been used during the years as for ADC production, unfavorable physicochemical properties impaired production ADCs optimal features....
Abstract Thienoindoles are a new proprietary class of highly potent DNA minor groove alkylating agents. This is characterized by fused thiophene ring whose intrinsic electron-withdrawing character provides nearly optimal increase in stability and potency subunits. Furthermore, the presence solubilizing moiety on portion compounds with physicochemical properties compatible deployment as antibody payloads. Extensive optimization this has led to identification toxin NMS-P528 sub-nanomolar IC50...
Abstract The rapidly growing field of Antibody-Drug Conjugates (ADCs) has recently spurred the study novel drug payloads. In particular, much interest been paid to identification cytotoxic agents, which differ in mechanism from anti-tubulin currently most commonly employed class for ADC coupling. Novel payloads ADC-based therapy should thus ideally possess highly potent activity with a diverse tubulin as well physicochemical properties, facilitate coupling antibodies. Duocarmycins are...
Abstract Most of the widely used anticancer drugs target elongation step DNA synthesis, either directly, for example by restricting pool dNTPs or acting as chain terminators following incorporation into nascent strands, indirectly, targeting enzymes that facilitate replication fork progression, intercalating and thereby creating a physical block to progression. The arrest forks induced these agents invariably results in strand breakage, which, while being potentially toxic normal...