Publications by authors named "Giovanni Cervi"

6 Publications

  • Page 1 of 1

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

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

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

Thieno[3,2-c]pyrazoles: a novel class of Aurora inhibitors with favorable antitumor activity.

Bioorg Med Chem 2010 Oct 25;18(19):7113-20. Epub 2010 Jul 25.

Nerviano Medical Sciences-Oncology, via Pasteur 10, 20014 Nerviano, Milan, Italy.

A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.
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http://dx.doi.org/10.1016/j.bmc.2010.07.048DOI Listing
October 2010

Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.

J Med Chem 2009 Aug;52(16):5152-63

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

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
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http://dx.doi.org/10.1021/jm9006559DOI Listing
August 2009

Bicyclic carbohydrate-derived scaffolds for combinatorial libraries.

Bioorg Med Chem 2006 May 24;14(10):3349-67. Epub 2006 Jan 24.

Dipartimento di Biotecnologie e Bioscienze, UniversitĂ  degli Studi di Milano-Bicocca, Piazza della Scienza 2, I-20126 Milano, Italy.

A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized as ester, ether, and carbamate, the amino group in the second cycle (C-3' position) was functionalized as amide, sulfonamide, and ureido- and thioureido-derivatives. The compounds synthesized on the solid phase were tested for their antiproliferative activity on tumor cell lines.
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http://dx.doi.org/10.1016/j.bmc.2005.12.055DOI Listing
May 2006