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Dive into the research topics where Enrico Pesenti is active.

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Featured researches published by Enrico Pesenti.


Molecular Cancer Therapeutics | 2007

PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer

Patrizia Carpinelli; Roberta Ceruti; Maria Laura Giorgini; Paolo Cappella; Laura Gianellini; Valter Croci; Anna Degrassi; Gemma Texido; Maurizio Rocchetti; Paola Vianello; Luisa Rusconi; Paola Storici; Paola Zugnoni; Claudio Arrigoni; Chiara Soncini; Cristina Alli; Veronica Patton; Aurelio Marsiglio; Dario Ballinari; Enrico Pesenti; Daniele Fancelli; Jürgen Moll

PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition–related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status–dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser10 is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers. [Mol Cancer Ther 2007;6(12):3158–68]


Clinical Cancer Research | 2006

PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity.

Chiara Soncini; Patrizia Carpinelli; Laura Gianellini; Daniele Fancelli; Paola Vianello; Luisa Rusconi; Paola Storici; Paola Zugnoni; Enrico Pesenti; Valter Croci; Roberta Ceruti; Maria Laura Giorgini; Paolo Cappella; Dario Ballinari; Francesco Sola; Mario Varasi; Rodrigo Bravo; Jürgen Moll

Purpose: Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy. Experimental Design: The activity of PHA-680632 was assayed in a biochemical ATP competitive kinase assay. A wide panel of cell lines was evaluated for antiproliferative activity. Cell cycle analysis. Immunohistochemistry, Western blotting, and Array Scan were used to follow mechanism of action and biomarker modulation. Specific knockdown of the targets by small interfering RNA was followed to validate the observed phenotypes. Efficacy was determined in different xenograft models and in a transgenic animal model of breast cancer. Results: PHA-680632 is active on a wide range of cancer cell lines and shows significant tumor growth inhibition in different animal tumor models at well-tolerated doses. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. Histone H3 phosphorylation in Ser10 is mediated by Aurora B kinase, and our kinetic studies on its inhibition by PHA-680632 in vitro and in vivo show that phosphorylation of histone H3 is a good biomarker to follow activity of PHA-680632. Conclusions: PHA-680632 is the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic. On treatment, different cell lines respond differentially, suggesting the absence of critical cell cycle checkpoints that could be the basis for a favorable therapeutic window.


Blood | 2008

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

Artur Gontarewicz; Stefan Balabanov; Gunhild Keller; Riccardo Colombo; Alessio Graziano; Enrico Pesenti; Daniel Benten; Carsten Bokemeyer; Walter Fiedler; Jurgen Moll; Tim H. Brümmendorf

The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34(+) cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.


Cancer Research | 2010

Targeting the Mitotic Checkpoint for Cancer Therapy with Nms-P715, an Inhibitor of Mps1 Kinase.

Riccardo Colombo; Marina Caldarelli; Milena Mennecozzi; Maria Laura Giorgini; Francesco Sola; Paolo Cappella; Claudia Perrera; Stefania Re Depaolini; Luisa Rusconi; Ulisse Cucchi; Nilla Avanzi; Jay Aaron Bertrand; Roberto Bossi; Enrico Pesenti; Arturo Galvani; Antonella Isacchi; Francesco Colotta; Daniele Donati; Jurgen Moll

MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.


Nature Chemical Biology | 2008

A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.

Alessia Montagnoli; Barbara Valsasina; Valter Croci; Maria Menichincheri; Sonia Rainoldi; Vanessa Marchesi; Marcello Tibolla; Pierluigi Tenca; Deborah Brotherton; Clara Albanese; Veronica Patton; Rachele Alzani; Antonella Ciavolella; Francesco Sola; Antonio Molinari; Daniele Volpi; Nilla Avanzi; Francesco Fiorentini; Marina Cattoni; Sandra Healy; Dario Ballinari; Enrico Pesenti; Antonella Isacchi; Jurgen Moll; Aaron Bensimon; Ermes Vanotti; Corrado Santocanale

Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.


Clinical Cancer Research | 2004

In Vivo Assessment of Antiangiogenic Activity of SU6668 in an Experimental Colon Carcinoma Model

Pasquina Marzola; Anna Degrassi; Laura Calderan; Paolo Farace; Caterina Crescimanno; Elena Nicolato; Anna Giusti; Enrico Pesenti; Andrea Terron; Andrea Sbarbati; Tinya Abrams; Lesley J. Murray; Francesco Osculati

Purpose: The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1. Experimental Design: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment. Results: DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment. Conclusions: DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.


Journal of Medicinal Chemistry | 2010

Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors

Italo Beria; Dario Ballinari; Jay Aaron Bertrand; Daniela Borghi; Roberto Bossi; Maria Gabriella Brasca; Paolo Cappella; Michele Caruso; Walter Ceccarelli; Antonella Ciavolella; Cinzia Cristiani; Valter Croci; Anna De Ponti; Gabriele Fachin; Ron Ferguson; Jacqueline Lansen; Jurgen Moll; Enrico Pesenti; Helena Posteri; Rita Perego; Maurizio Rocchetti; Paola Storici; Daniele Volpi; Barbara Valsasina

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.


Molecular Oncology | 2014

The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition.

Elena Ardini; Roberta Bosotti; Andrea Lombardi Borgia; Cristina De Ponti; Alessio Somaschini; Rosaria Cammarota; Nadia Amboldi; Laura Raddrizzani; Andrea Milani; Paola Magnaghi; Dario Ballinari; Daniele Casero; Fabio Gasparri; Patrizia Banfi; Nilla Avanzi; Maria Beatrice Saccardo; Rachele Alzani; Tiziano Bandiera; Eduard Felder; Daniele Donati; Enrico Pesenti; Andrea Sartore-Bianchi; Marcello Gambacorta; Marco A. Pierotti; Salvatore Siena; Silvio Veronese; Arturo Galvani; Antonella Isacchi

The NTRK1 gene encodes Tropomyosin‐related kinase A (TRKA), the high‐affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3‐NTRK1) resulting in expression of the oncogenic chimeric protein TPM3‐TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3‐TRKA protein and is hypersensitive to TRKA kinase inhibition. We report the detailed characterization of the TPM3‐NTRK1 genomic rearrangement in KM12 cells and through a cellular screening approach, the identification of NMS‐P626, a novel highly potent and selective TRKA inhibitor. NMS‐P626 suppressed TPM3‐TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors.


Molecular Cancer Therapeutics | 2012

NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies.

Barbara Valsasina; Italo Beria; Cristina Alli; Rachele Alzani; Nilla Avanzi; Dario Ballinari; Paolo Cappella; Michele Caruso; Alessia Casolaro; Antonella Ciavolella; Ulisse Cucchi; Anna De Ponti; Eduard R. Felder; Francesco Fiorentini; Arturo Galvani; Laura Gianellini; Maria Laura Giorgini; Antonella Isacchi; Jacqueline Lansen; Enrico Pesenti; Simona Rizzi; Maurizio Rocchetti; Francesco Sola; Jurgen Moll

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings. Mol Cancer Ther; 11(4); 1006–16. ©2012 AACR.


Molecular Cancer Therapeutics | 2016

Entrectinib, a Pan-TRK, ROS1 and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Elena Ardini; Maria Menichincheri; Patrizia Banfi; Roberta Bosotti; Cristina De Ponti; Romana Pulci; Dario Ballinari; Marina Ciomei; Gemma Texido; Anna Degrassi; Nilla Avanzi; Nadia Amboldi; Maria Beatrice Saccardo; Daniele Casero; Paolo Orsini; Tiziano Bandiera; Luca Mologni; David Anderson; Ge Wei; Jason B. Harris; Jean-Michel Vernier; Gang Li; Eduard Felder; Daniele Donati; Antonella Isacchi; Enrico Pesenti; Paola Magnaghi; Arturo Galvani

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non–small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drugs pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. Mol Cancer Ther; 15(4); 628–39. ©2016 AACR.

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Paolo Orsini

National University of Ireland

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