Publications by authors named "Daniele Donati"

68 Publications

The opinions and feelings about their educational needs and role of familial caregivers of Parkinson's Disease patients: a qualitative study.

Acta Biomed 2020 11 30;91(12-S):e2020002. Epub 2020 Nov 30.

Department of Health, Life and Environmental Sciences, University of L'Aquila, Edificio Rita Levi Montalcini - Via G. Petrini - 67100 L'Aquila, Italy.

Background And Aim Of The Work: In the advanced stages of Parkinson's Disease, patients need complex care and support, especially at home, where they often receive assistance by familial caregivers. However, caregivers may be or feel unable to cope with their role and, despite the needs of caregivers are often assessed in the literature, their opinions and feelings about these needs are not widely explored yet. This study aimed at exploring the opinions and feelings about their educational needs and role of familial caregivers of Parkinson's Disease patients.

Methods: A qualitative study was conducted from October to December 2017 in a polyclinic of central Italy. Fourteen caregivers voluntarily participated in the study; semi-structured face-to-face interviews were conducted, and audio recorded until data saturation. Two investigators reviewed the transcribed notes, created Meaning Units, Sub-categories and finally the Categories with emerged themes.

Results: The analysis of the 14 interviews generated three categories: supportiveness of healthcare educational programs; sense of inability to manage caregiver tasks; need for interaction with other familial caregivers.

Conclusions: The caregivers declared their belief that healthcare educational courses can be useful in helping them live and understand the caregiving tasks and expressed their need to share their experiences with other caregivers. In fact, they often they felt abandoned and poorly trained for the patient's management at the home. The clinical practice should allow healthcare professionals to meet the training and emotional needs of caregivers and create a trust relationship with them to make caregivers skilled in caring for patients.
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http://dx.doi.org/10.23750/abm.v91i12-S.10264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023112PMC
November 2020

Effectiveness of implementing link nurses and audits and feedback to improve nurses' compliance with standard precautions: A cluster randomized controlled trial.

Am J Infect Control 2020 10 13;48(10):1204-1210. Epub 2020 Mar 13.

Research Unit Nursing Science, Campus Bio-Medico University of Rome, Rome, Italy.

Background: To prevent health care-associated infections, health organizations recommend that health care workers stringently observe standard precautions (SPs). Nevertheless, compliance with SPs is still suboptimal, emphasizing the need for improvement interventions.

Methods: A cluster randomized controlled trial with a pretest-post-test design was conducted with 121 clinical nurses who worked in different wards of a university hospital. The intervention group (n = 61) had 3 infection control link nurses nominated and attended systematic audits and feedback. The control group (n = 60) received only the standard multimodal approach used in the hospital. Pre- and post-test assessment of SPs compliance was performed via the World Health Organization observational hand hygiene form and Compliance with Standard Precaution Scale Italian version.

Results: At the post-test, nurses in the intervention group reported significantly increased compliance with hand hygiene, whereas no significant improvement was found in the control group. Nurses in both groups reported significantly increased Compliance with Standard Precaution Scale Italian version scores; however, a higher increase and practical significance was observed in the intervention group. Participants who improved their scores were also compared between groups, showing a significantly greater increase of individual scores in intervention group compared to the control group.

Conclusions: The findings of this study provide significant practical implications for hospitals seeking to improve compliance with SPs among nurses, showing the effectiveness of using infection control link nurses combined with systematic audits and feedback.
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http://dx.doi.org/10.1016/j.ajic.2020.01.017DOI Listing
October 2020

Stress-related vulnerability and usefulness of healthcare education in Parkinson's disease: The perception of a group of family caregivers, a cross-sectional study.

Appl Nurs Res 2020 02 11;51:151186. Epub 2019 Sep 11.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy. Electronic address:

Parkinson's Disease is associated with a high assistive complexity, thus generating in caregivers a burden proportional to the intensity of the care provided. This study aims to evaluate whether the stress-related level of caregivers is related to their perception of the need for healthcare education. A cross-sectional study was conducted on 69 family caregivers that completed the Stress-related Vulnerability Scale (SVS scale) with a tool of proposed interventions stratified according to caregivers' need as "nothing", "somewhat", "moderately" and "extremely". A direct association between the SVS scale and the perception of the usefulness of interventions was detected, and significant differences were observed for "Caregivers tele-support group" and "Peer-led support group" interventions, thus suggesting an important role for caregivers' emotional status in considering of training courses. Caregivers are split between low vulnerability, with minimal perception of training need, and high burden state with the acute necessity of support to manage patients.
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http://dx.doi.org/10.1016/j.apnr.2019.151186DOI Listing
February 2020

Experiences of compliance with standard precautions during emergencies: A qualitative study of nurses working in intensive care units.

Appl Nurs Res 2019 10 30;49:35-40. Epub 2019 Jul 30.

Research Unit Nursing Science, Campus Bio-Medico University of Rome, via Álvaro del Portillo 21, 00128 Rome, Italy. Electronic address:

Aim To explore factors that influence intensive care nurses' experiences of being compliant with standard precautions (SP) during emergencies.

Background: Intensive care nurses can be exposed to a greater risk of biohazardous exposure during an emergency. The primary strategy to address the complex variety of biological hazards in clinical practice is represented by the implementation of SP guidelines. Previous research has indicated that nurses' compliance rates with SPs are suboptimal, but no study has focused on the factors influencing compliance during an emergency.

Design: A descriptive qualitative study was conducted in an Italian university hospital with 19 intensive care nurses who had at least two years of work experience in critical care. The nurses were interviewed in four focus groups and were asked about their experiences of being compliant with SPs during an emergency. Data were analyzed using conventional content analysis.

Results: Three themes emerged: conflict, competencies, and context. Conflict was reported regarding the need to save the patient and the need for self-protection through the use of SPs. In particular, nurses had to manage the pressure of limited time. Competencies were identified by nurses' knowledge, attitude, skills, training, and experience. Context was related to the work and organizational conditions during the emergency, including overcrowding.

Conclusion: To support intensive care nurses' compliance with SPs during emergencies, conflict, competencies, and context should be audited regularly in clinical practice. The findings of this study could inform infection control programs and training that targets intensive care nurses.
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http://dx.doi.org/10.1016/j.apnr.2019.07.007DOI Listing
October 2019

The transmission dynamic of Madariaga Virus by bayesian phylogenetic analysis: Molecular surveillance of an emergent pathogen.

Microb Pathog 2019 Jul 25;132:80-86. Epub 2019 Apr 25.

Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, Italy.

Madariaga Virus (MADV) is an emergent Alphavirus of the eastern equine encephalitis virus (EEEV) strain complex causing epizootic epidemics. In this study the genetic diversity and the transmission dynamics of Madariaga virus has been investigated by Bayesian phylogenetics and phylodynamic analysis. A database of 32 sequences of MADV group structural polyprotein were downloaded from GenBank, aligned manually edited by Bioedit Software. ModelTest v. 3.7 was used to select the simplest evolutionary model that adequately fitted the sequence data. Neighbor-joining tree was generated using MEGA7. The phylogenetic signal of the dataset was tested by the likelihood mapping analysis. The Bayesian phylogenetic tree was built using BEAST. Selective pressure analysis revealed one positive selection site. The phylogenetic trees showed two main clusters. In particular, Lineage II showed an epizootic infection in monkeys and Lineage III, including 2 main clusters (IIIa and IIIB), revealing an epizootic infection in humans in Haiti and an epizootic infection in humans in Venezuela during the 2016, respectively. The Bayesian maximum clade credibility tree and the time of the most common recent ancestor estimates, showed that the root of the tree dated back to the year 346 with the probable origin in Brazil. Gene flow analysis revealed viral exchanges between different neighbor countries of South America. In conclusion, Bayesian phylogenetic and phylodynamic represent useful tools to follow the transmission dynamic of emergent pathogens to prevent new epidemics spreading worldwide.
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http://dx.doi.org/10.1016/j.micpath.2019.04.039DOI Listing
July 2019

Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.

ACS Med Chem Lett 2019 Apr 13;10(4):534-538. Epub 2019 Mar 13.

Oncology, Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered ()- (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (: 0.016 μM) and cellular (IC: 0.027 μM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466814PMC
April 2019

Compliance with Standard Precautions among Clinical Nurses: Validity and Reliability of the Italian Version of the Compliance with Standard Precautions Scale (CSPS-It).

Int J Environ Res Public Health 2019 01 4;16(1). Epub 2019 Jan 4.

Research Unit Nursing Science, Campus Bio-Medico University of Rome, 00128 Rome, Italy.

Background: The compliance with Standard Precautions (SPs) guidelines, as a primary strategy for the prevention of healthcare associated infections, is still suboptimal among healthcare providers. However, no instrument measuring nurses' compliance with SPs is available in Italian. This study aims to assess the validity and reliability of the Compliance with Standard Precaution Scale⁻Italian version (CSPS-It) among clinical nurses.

Methods: The study consisted of two phases: (1) translation and cross-cultural adaptation of the CSPS; (2) validity and reliability evaluation of the CSPS-It. Confirmatory factor analysis (CFA) and hypothesis testing were performed to evaluate the construct validity. Cronbach's alpha, intra-class correlation coefficient of test-retest scores, and item-total correlations were computed to establish reliability.

Results: The CSPS-It showed a sound validity and reliability. The unidimensional model tested at CFA yielded acceptable fit indices. The hypothesis testing supported better nurses' compliance based on participation in at least one training course on SPs.

Conclusions: The CSPS-It is a valid and reliable instrument for measuring the compliance with SPs among clinical nurses. This version will allow for the conduction of further studies in favor of progress in this specific field of research. Managers should pay greater attention in monitoring compliance with SPs among clinical nurses.
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http://dx.doi.org/10.3390/ijerph16010121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339176PMC
January 2019

The effects of a multidisciplinary education course on the burden, health literacy and needs of family caregivers.

Appl Nurs Res 2018 12 18;44:100-106. Epub 2018 Oct 18.

Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, Rome, Italy.

Chronic diseases are mostly managed by family caregivers that often face the "caregiver burden". This study aimed to understand whether a multidisciplinary theoretical-practical training course could influence the burden, health literacy and needs of caregivers. Seventy-six familial caregivers were asked to complete the Caregiver Burden Inventory-CBI, Caregiver Needs Assessment-CNA, and Health Literacy Questionnaire-HLQ, before and after the course. A significant decrease in CBI and an increase of CNA were observed. However, a significantly higher rate of CBI decrease and a lower increase of CNA were detected in the neurological compared to the oncological group (p = 0.001). Moreover, the ability of the participants to look for and find health information significantly improved. The course contrasted caregivers' burden, increased their search for health information, and revealed their requiring of training and emotional and social support. Caregiver education plays a pivotal role in the management of chronic patients, enhancing the quality of life of both patients and caregivers.
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http://dx.doi.org/10.1016/j.apnr.2018.10.004DOI Listing
December 2018

BRASS score and complex discharge: a pilot study

Acta Biomed 2018 01 16;88(4):414-425. Epub 2018 Jan 16.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy

Aims: A highly functional continuity of patient care, which is linked to the reduction of the risk of long-term hospitalization, above all for 'at-risk' patients. Research into an objective, reliable instrument for redirecting individual results to organizational aims to extend the entire country, is a fundamental step to move from a reactive assistance approach to a pro-active one.

Methods: An observational and descriptive retrospective study was carried out July - November 2014 in two Italian state hospitals, completing the BRASS Index within 48/72 hours of admission.

Results: The study group consisted of 122 inpatients. A correlation presented itself, albeit low (ñ=0.05191), between age and the number of 'revolving door' admissions; a medium correlation (ñ=0.485131) between age and risk band (according to BRASS).

Conclusions: The BRASS Index is straightforward and swift, and can prove a valuable tool in directing nurses' attention to those patients most at risk of prolonged hospitalization.
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http://dx.doi.org/10.23750/abm.v88i4.6191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166170PMC
January 2018

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

J Med Chem 2016 Apr 30;59(7):3392-408. Epub 2016 Mar 30.

Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00064DOI Listing
April 2016

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

Mol Cancer Ther 2016 04 3;15(4):628-39. Epub 2016 Mar 3.

Nerviano Medical Sciences srl, Nerviano, Milan, Italy.

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 drug's 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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http://dx.doi.org/10.1158/1535-7163.MCT-15-0758DOI Listing
April 2016

Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

J Med Chem 2015 Sep 26;58(17):6875-98. Epub 2015 Aug 26.

Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00680DOI Listing
September 2015

Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.

Bioorg Med Chem 2015 May 28;23(10):2387-407. Epub 2015 Mar 28.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
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http://dx.doi.org/10.1016/j.bmc.2015.03.059DOI Listing
May 2015

Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers.

Chemistry 2015 Apr 17;21(18):6921-9. Epub 2015 Mar 17.

Università degli Studi di Milano, Dipartimento di Chimica, Via C. Golgi, 19, 20133, Milan (Italy), Fax: (+39) 02-5031-4072.

Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvβ3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVβ3-) and its subclone CCRF-CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVβ3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.
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http://dx.doi.org/10.1002/chem.201500158DOI Listing
April 2015

Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.

J Med Chem 2014 Dec 12;57(24):10443-54. Epub 2014 Dec 12.

Oncology, Nerviano Medical Sciences S.r.l. , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
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http://dx.doi.org/10.1021/jm501313xDOI Listing
December 2014

Optimization of diarylthiazole B-raf inhibitors: identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect.

ChemMedChem 2015 Feb 27;10(2):276-95. Epub 2014 Nov 27.

Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI) (Italy).

Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R(1) and R(2) groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg(-1) ); it is therefore a suitable candidate for preclinical development.
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http://dx.doi.org/10.1002/cmdc.201402424DOI Listing
February 2015

Synthesis and Structure-Activity Relationships of α-Amino-γ-lactone Ketolides: A Novel Class of Macrolide Antibiotics.

ACS Med Chem Lett 2014 Oct 15;5(10):1133-7. Epub 2014 Aug 15.

Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.

An efficient synthesis of α-amino-γ-lactone ketolide (3) was developed, which provided a versatile intermediate for the incorporation of a variety of aryl and heteroaryl groups onto the C-21 position of clarithromycin via HBTU-mediated amidation. The biological data for this important new class of macrolides revealed significantly potent activity against erythromycin-susceptible strains as well as efflux-resistant and erythromycin MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted γ-lactone ketolides have potential as a next generation macrolide antibiotics.
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http://dx.doi.org/10.1021/ml500279kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190632PMC
October 2014

Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.

Bioorg Med Chem 2014 Sep 21;22(17):4998-5012. Epub 2014 Jun 21.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
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http://dx.doi.org/10.1016/j.bmc.2014.06.025DOI Listing
September 2014

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

Mol Oncol 2014 Dec 12;8(8):1495-507. Epub 2014 Jun 12.

Nerviano Medical Sciences S.r.l., Nerviano (Milan), Italy.

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. Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors.
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http://dx.doi.org/10.1016/j.molonc.2014.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528583PMC
December 2014

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.

Bioorg Med Chem 2013 Dec 2;21(23):7364-80. Epub 2013 Oct 2.

Oncology, Nerviano Medical Sciences, viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address:

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
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http://dx.doi.org/10.1016/j.bmc.2013.09.054DOI Listing
December 2013

Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90).

Bioorg Med Chem 2013 Nov 19;21(22):7047-63. Epub 2013 Sep 19.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. Electronic address:

Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.
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http://dx.doi.org/10.1016/j.bmc.2013.09.018DOI Listing
November 2013

Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death.

Nat Chem Biol 2013 Sep 28;9(9):548-56. Epub 2013 Jul 28.

Business Unit Oncology, Nerviano Medical Sciences, Nerviano, Italy.

VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with autophagy and induced cancer cell death. The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target.
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http://dx.doi.org/10.1038/nchembio.1313DOI Listing
September 2013

NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases.

Clin Cancer Res 2013 Jul 14;19(13):3520-32. Epub 2013 May 14.

Department of Biotechnology, Nerviano Medical Sciences Srl, Nerviano (MI), Italy.

Purpose: Recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB).

Experimental Design: Here is described a detailed biochemical and crystallographic characterization of NMS-E973. Mechanism-based anticancer activity was described in cell models, including models of resistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver, and brain. In vivo activity and pharmacodynamics, as well as the pharmacokinetic/pharmacodynamic relationships, were evaluated in xenografts, including an intracranially implanted melanoma model.

Results: NMS-E973, representative of a novel isoxazole-derived class of Hsp90 inhibitors, binds Hsp90α with subnanomolar affinity and high selectivity towards kinases, as well as other ATPases. It possesses potent antiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selective retention in tumor tissue and ability to cross the BBB. NMS-E973 induces tumor shrinkage in different human tumor xenografts, and is highly active in models of resistance to kinase inhibitors. Moreover, consistent with its brain penetration, NMS-E973 is active also in an intracranially implanted melanoma model.

Conclusions: Overall, the efficacy profile of NMS-E973 suggests a potential for development in different clinical settings, including tumors that have become resistant to molecular targeted agents, particularly in cases of tumors which reside beyond the BBB.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3512DOI Listing
July 2013

Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships.

J Med Chem 2013 Jan 4;56(2):437-50. Epub 2013 Jan 4.

Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.
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http://dx.doi.org/10.1021/jm3013213DOI Listing
January 2013

Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders.

Bioorg Med Chem Lett 2011 Sep 30;21(18):5562-7. Epub 2011 Jun 30.

GlaxoSmithKline Medicine Research Centre, Via A. Fleming, 4, 37135 Verona, Italy.

The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.086DOI Listing
September 2011

Synthesis and biological activity of a novel class nicotinic acetylcholine receptors (nAChRs) ligands structurally related to anatoxin-a.

Bioorg Med Chem Lett 2011 Sep 20;21(18):5423-7. Epub 2011 Jul 20.

Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.

The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with α1, α7 and α3β4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.127DOI Listing
September 2011

Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors.

Bioorg Med Chem Lett 2011 Aug 14;21(15):4507-11. Epub 2011 Jun 14.

Nerviano Medical Sciences srl, Business Unit Oncology, Nerviano, MI, Italy.

The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.
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http://dx.doi.org/10.1016/j.bmcl.2011.05.122DOI Listing
August 2011

Synthesis and structure-activity relationship of new 1,5-dialkyl-1,5-benzodiazepines as cholecystokinin-2 receptor antagonists.

Bioorg Med Chem 2011 Jul 6;19(14):4257-73. Epub 2011 Jun 6.

GlaxoSmithKline, Medicines Research Centre, Via A. Fleming, 4, 37100 Verona, Italy.

This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.
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http://dx.doi.org/10.1016/j.bmc.2011.05.057DOI Listing
July 2011

Discovery and biological characterization of (2R,4S)-1'-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4'-bipiperidine-1-carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate.

J Med Chem 2011 Feb 13;54(4):1071-9. Epub 2011 Jan 13.

GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.
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http://dx.doi.org/10.1021/jm1013264DOI Listing
February 2011