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

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.

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

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).

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

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.

[Effectiveness of a nurse-led educational intervention for patients admitted for acute coronary syndrome].

Objective: To assess the effectiveness of a nurse-led class with phone follow-up, to help patients achieve lifestyle changes after an acute coronary syndrome (ACS).

Methods: Each patient < or = 75 years, admitted to a intensive cardiac care unit (ICCU) for ACS from September 2003 to December 2004, who attended the education class (case) was matched with two patients paired for age, sex and admission time, admitted for ACS to ICCUs in the other hospitals in the same area (controls). One year later the two groups were blindly interviewed on the phone, using a structured questionnaire about their lifestyles.

Phosphorylation of TCTP as a marker for polo-like kinase-1 activity in vivo.

Polo-like kinase 1 (PLK1) is the master regulator of mitosis and a target for anticancer therapy. To develop a marker of PLK1 activity in cells and tumour tissues, this study focused on translational controlled tumour protein (TCTP) and identified serine 46 as a site phosphorylated by PLK1 in vitro. Using an antibody raised against phospho-TCTP-Ser46, it was demonstrated that phosphorylation at this site correlates with PLK1 level and kinase activity in cells.

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.

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.

[How to increase patient knowledge of their coronary heart disease: impact of an educational meeting led by nurses].

Background: Most patients discharged after an acute coronary event or a coronary revascularization do not have adequate knowledge of the nature of their disease and of the importance of a correct lifestyle. The aim of this study was to assess the effectiveness of an educational intervention led by nurses for patients admitted to hospital for coronary heart disease (CHD).

Methods: Since May 2003, regular health education meetings for inpatients with CHD and their relatives have been held by the nurses of the Cardiology Division of the Desio hospital.

[An health education program for patients admitted to CCU for an acute coronary event].

Unlabelled: In spite of the broad recognition of the importance of health education, time for structured one-to -one initiatives of health education during the hospital stay is limited. The organization of an health education meeting for patients admitted to CCU for an acute coronary event is described.

Methods: The planning and implementation of the initiative lasted two years and involved 7 nurses and one doctor.

[Knowledge and lifestyles of patients: a survey on patients admitted with acute coronary syndrome in the CCU of an Italian hospital].

Aim And Methods: The lifestyles before hospital admission, knowledge on their illness and lifestyles after the acute coronary event were analysed with questionnaires, in three different samples of patients: a. all the patients admitted for acute coronary event from may 2003 to may 2005 to explore lifestyles before acute coronary event (416 patients) b. all the patients admitted from may 2003 to april 2004 (before the start of health information meetings organised by nurses), to explore the knowledge of the illness and its causes (132 patients) c.