Publications by authors named "Marcella Nesi"

9 Publications

  • Page 1 of 1

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

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

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

Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors.

Biochemistry 2010 Aug;49(32):6813-25

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

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the development of several human cancers and, as a result, is a recognized target for the development of small-molecule inhibitors for the treatment of ALK-positive malignancies. Here, we present the crystal structures of the unphosphorylated human ALK kinase domain in complex with the ATP competitive ligands PHA-E429 and NVP-TAE684. Analysis of these structures provides valuable information concerning the specific characteristics of the ALK active site as well as giving indications about how to obtain selective ALK inhibitors. In addition, the ALK-KD-PHA-E429 structure led to the identification of a potential regulatory mechanism involving a link made between a short helical segment immediately following the DFG motif and an N-terminal two-stranded beta-sheet. Finally, mapping of the activating mutations associated with neuroblastoma onto our structures may explain the roles these residues have in the activation process.
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http://dx.doi.org/10.1021/bi1005514DOI Listing
August 2010

Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.

Bioorg Med Chem 2010 Mar 25;18(5):1844-53. Epub 2010 Jan 25.

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

We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.
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http://dx.doi.org/10.1016/j.bmc.2010.01.042DOI Listing
March 2010

6-Substituted pyrrolo[3,4-c]pyrazoles: an improved class of CDK2 inhibitors.

ChemMedChem 2007 Jun;2(6):841-52

Oncology Business Unit, Department of Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano MI, Italy.

We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.
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http://dx.doi.org/10.1002/cmdc.200600302DOI Listing
June 2007

A practical synthesis of the major 3-hydroxy-2-pyrrolidinone metabolite of a potent CDK2/cyclin A inhibitor.

Bioorg Med Chem Lett 2006 Jun 17;16(12):3205-8. Epub 2006 Apr 17.

Department of Chemistry, Oncology Business Unit, Nerviano Medical Sciences, Viale Pasteur 10-20014 Nerviano, MI, Italy.

The synthesis of the major metabolite of a potent 3-aminopyrazole CDK2/cyclin A inhibitor is presented. A stereoconservative approach starting from malic acid was employed to construct the hydroxy-substituted pyrrolidinone moiety. In the key step of the synthesis the use of cyanoborohydride immobilized on Amberlyst 26 in trifluoroethanol represented a valid alternative to conventional solution-phase reducing agents.
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http://dx.doi.org/10.1016/j.bmcl.2006.03.051DOI Listing
June 2006

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization.

J Med Chem 2005 Apr;48(8):2944-56

Department Chemistry, Nerviano Medical Sciences, BU-Oncology and BU-Preclinical Science, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.
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http://dx.doi.org/10.1021/jm0408870DOI Listing
April 2005