MARIO VARASI

Education and PHD/Masters/Courses

1970-1976: Doctoral studies (laureato) in Medicinal Chemistry and Technology, University of Rome, Italy [ 110/110 summa cum laude Palo Alto, CA-USA ] . 1977-1979: Post-doctoral research fellow, Institute of Organic Chemistry, Syntex Research-

Titles (included other positions covered)

1979-1981 Organic Chemistry Lab. Head, R&D-Zambeletti SpA, Baranzate di Bollate, Milano-Italy. 1981-1983 Organic Chemistry Lab. Head, Preclinical Research-Dow Lepetit, Via Durando, 38. Milano, Italy. 1983-1994 CNS-Med. Chemistry Lab. Head, R&D Farmitalia Carlo Erba, Via Imbonati, 24. Milano, Italy. 1994-1996 CNS-Med. Chemistry Department Head-Pharmacia & Upjohn, Viale Pasteur, 10. Nerviano (MI), Italy 1997 Deputy Director of the Chemistry Department and acting Director of Preclinical CNS Research, Pharmacia & Upjohn- Nerviano (MI), Italy. 1998-2005 Director of Chemistry Department, Discovery Research Oncology Pharmacia and Pharmacia Italia S.p.A.-Pfizer Group, and Nerviano Medical Sciences. Nerviano (MI), Italy. 2005- 2009 Director of Chemistry Department, Genextra S.p.A. Milano (Italy)

Clinical Activities carried out at IEO

NA

Research Activities carried out at IEO

2009-present: Director of Drug Discovery Unit-Dept. of Experimental Oncology (Epigenetics, Cancer Stem cell)

Passed Clinical and Research Activities

• Design and synthesis of novel antidepressant agents, anticonvulsants, 5-HT3 antagonists , antiexcitotoxin agents (EAA antagonists and kynurenine-3-hydroxylase inhibitors) and A beta peptide aggregation inhibitors for Alzheimer. • Project Leader for the following projects: -5-HT3 antagonists (clinical candidate identified), -antiexcitotoxin agents (NMDA antagonists and Kynurenine pathway interfering agents) -anticonvulsants (clinical candidates identified). -antiexcitotoxin agents. Contribution to the discovery and identification of clinical candidates in the areas of epilepsy, parkinson and neuropatic pain. • Discovery and development of molecular targeted anticancer agents, development of targeted libraries for the kinase platform. Contribution to the discovery and identification of clinical candidates in the area of CDK2, CDC7 and Aurora, and HDAC inhibitor and mitochondrial medicine. • • • Experience of leading Department(s) of up to 120 scientists (Medicinal Chemistry, Analytical Chemistry, Combinatorial Chemistry, Structural Chemistry, Molecular Modeling & Design and Research Informatics-Biochemistry, Cell Biology and In vivo pharmacology). Focus on the optimisation of workflow and resource utilization, recruit and retain first class scientists to secure optimal support of the drug discovery process. Author of ≈ 80 papers and holder of ≈ 80 patents.

Awards and other Recognitions

-Recipient of the Upjohn Award (2001).“Based upon demonstration of the Best-Managed Behaviors and special accomplishments” - Recipient of the “Medaglia G Giacomello” Soc. Chim. Italiana_Div. Di Chimica Farmaceutica (2012) for his many and important contributions to the advancement of Medicinal Chemistry in a long, distinguished and varied career as an industrial medicinal chemistry researcher.

Publications

1.

Florian Thaler, Mario Varasi, Giacomo Carenzi, Andrea Colombo, Agnese Abate, Chiara Bigogno, Roberto Boggio, Simone Carrara, Tiziana Cataudella, Roberto Dal Ciro Mercurio

Spiro[chromane-2,4 ′

Zuffo, Veronica Reali, Stefania Vultaggio, Giulio Dondio, Stefania Gagliardi, Saverio Minucci,

-piperidine]-Based Histone Deacetylase Inhibitors with Improved in vivo Activity

ChemMedChem (2012), 7(4), 709-721. 2.

3.

Giuseppe La Regina, Ruoli Bai, Willeke Rensen, Antonio Coluccia, Francesco Piscitelli, Valerio Gatti, Alessio Bolognesi, Antonio Lavecchia, Ilaria Granata, Amalia Porta, Bruno Maresca, Alessandra Soriani, Maria Luisa Iannitto, Marisa Mariani, Angela Santoni, Andrea Brancale, Cristiano Ferlini, Giulio Dondio, Mario Varasi, Ciro Mercurio, Ernest Hamel, Patrizia Lavia, Ettore Novellino, and Romano Silvestri

Design and Synthesis of 2-Heterocyclyl-3-arylthio-1

H

-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

Journal of Medicinal Chemistry (2011), 54(24), 8394–8406. Varasi, Mario; Thaler, Florian; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carenzi, Giacomo; Cataudella, Tiziana; Dal Zuffo, Roberto; Fulco, Maria Carmela; Rozio, Marco Giulio; Mai, Antonello; Dondio, Giulio; Minucci, Saverio; Mercurio, Ciro.

(HDAC) Inhibitors.

Discovery, Synthesis, and Pharmacological Evaluation of Spiropiperidine Hydroxamic Acid Based Derivatives as Structurally Novel Histone Deacetylase

Journal of Medicinal Chemistry (2011), 54(8), 3051-3064. 4.

Barker, John J.; Barker, Oliver; Courtney, Stephen M.; Gardiner, Mihaly; Hesterkamp, Thomas; Ichihara, Osamu; Mather, Owen; Montalbetti, Christian A. G. N.; Muller, Annett; Varasi, Mario; Whittaker, Mark; Yarnold, Christopher J.

Discovery of a novel Hsp90 inhibitor by fragment linking.

ChemMedChem (2010), 5(10), 1697-1700 5.

Thaler, Florian; Colombo, Andrea; Mai, Antonello; Amici, Raffaella; Bigogno, Chiara; Boggio, Roberto; Cappa, Anna; Carrara, Simone; Cataudella, Tiziana; Fusar, Fulvia; Gianti, Eleonora; di Ventimiglia, Samuele Joppolo; Moroni, Maurizio; Munari, Davide; Pain, Gilles; Regalia, Nickolas; Sartori, Luca; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, Ciro; Varasi, Mario.

ylacrylamides as Novel Histone Deacetylase Inhibitors.

Synthesis and Biological Evaluation of N-Hydroxyphenylacrylamides and N-Hydroxypyridin-2-

Journal of Medicinal Chemistry (2010), 53(2), 822-839. 6.

Barker, John J.; Barker, Oliver; Boggio, Roberto; Chauhan, Viddhata; Cheng, Robert K. Y.; Corden, Vincent; Courtney, Stephen M.; Edwards, Neil; Falque, Virginie M.; Fusar, Fulvia; Gardiner, Mihaly; Hamelin, Estelle M. N.; Hesterkamp, Thomas; Ichihara, Osamu; Jones, Richard S.; Mather, Owen; Mercurio, Ciro; Minucci, Saverio; Montalbetti, Christian A. G. N.; Muller, Annett; Patel, Deepti; Phillips, Banu G.; Varasi, Mario; Whittaker, Mark; Winkler, Dirk; Yarnold, Christopher J.

Fragment-based Identification of Hsp90 Inhibitors.

ChemMedChem (2009), 4(6), 963-966 7.

Menichincheri, Maria; Bargiotti, Alberto; Berthelsen, Jens; Bertrand, Jay A.; Bossi, Roberto; Ciavolella, Antonella; Cirla, Alessandra; Cristiani, Cinzia; Croci, Valter;

D'Alessio, Roberto; Fasolini, Marina; Fiorentini, Francesco; Forte, Barbara; Isacchi, Antonella; Martina, Katia; Molinari, Antonio; Montagnoli, Alessia; Orsini, Paolo; Orzi, Fabrizio; Pesenti, Enrico; Pezzetta, Daniele; Pillan, Antonio; Poggesi, Italo; Roletto, Fulvia; Scolaro, Alessandra; Tato, Marco; Tibolla, Marcellino; Valsasina, Barbara; Varasi, Mario; Volpi, Daniele; Santocanale, Corrado; Vanotti, Ermes.

Agents. 2. Lead Discovery.

First Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potent and Orally Active Antitumor

Journal of Medicinal Chemistry (2009), 52(2), 293 307 8.

Vanotti, Ermes; Amici, Raffaella; Bargiotti, Alberto; Berthelsen, Jens; Bosotti, Roberta; Ciavolella, Antonella; Cirla, Alessandra; Cristiani, Cinzia; D'Alessio, Roberto; Forte, Barbara; Isacchi, Antonella; Martina, Katia; Menichincheri, Maria; Molinari, Antonio; Montagnoli, Alessia; Orsini, Paolo; Pillan, Antonio; Roletto, Fulvia; Scolaro, Alessandra; Tibolla, Marcellino; Valsasina, Barbara; Varasi, Mario; Volpi, Daniele; Santocanale, Corrado.

Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potential Antitumor Agents. 1. Synthesis and Structure-Activity Relationships.

Journal of Medicinal Chemistry (2008), 51(3), 487-501 9.

Fancelli, Daniele; Moll, Juergen; Varasi, Mario; Bravo, Rodrigo; Artico, Roberta; Berta, Daniela; Bindi, Simona; Cameron, Alexander; Candiani, Ilaria; Cappella, Paolo; Carpinelli, Patrizia; Croci, Walter; Forte, Barbara; Giorgini, Maria Laura; Klapwijk, Jan; Marsiglio, Aurelio; Pesenti, Enrico; Rocchetti, Maurizio; Roletto, Fulvia; Severino, Dino; Soncini, Chiara; Storici, Paola; Tonani, Roberto; Zugnoni, Paola; Vianello, Paola.

Kinase Inhibitor with a Favorable Antitumor Kinase Inhibition Profile.

1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a Potent Aurora

Journal of Medicinal Chemistry (2006), 49(24), 7247-7251 10.

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

PHA-680632, a Novel Aurora Kinase Inhibitor with Potent Antitumoral Activity.

Clinical Cancer Research (2006), 12(13), 4080-4089 11.

Pevarello, Paolo; Brasca, Maria Gabriella; Orsini, Paolo; Traquandi, Gabriella; Longo, Antonio; Nesi, Marcella; Orzi, Fabrizio; Piutti, Claudia; Sansonna, Pietro; Varasi, Mario; Cameron, Alexander; Vulpetti, Anna; Roletto, Fulvia; Alzani, Rachele; Ciomei, Marina; Albanese, Clara; Pastori, Wilma; Marsiglio, Aurelio; Pesenti, Enrico; Fiorentini, Francesco; Bischoff, Jim R.; Mercurio, Ciro.

3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 2. Lead Optimization.

Journal of Medicinal Chemistry (2005), 48(8), 2944-2956. 12.

Fancelli, Daniele; Berta, Daniela; Bindi, Simona; Cameron, Alexander; Cappella, Paolo; Carpinelli, Patrizia; Catana, Cornel; Forte, Barbara; Giordano, Patrizia; Giorgini, Maria Laura; Mantegani, Sergio; Marsiglio, Aurelio; Meroni, Maurizio; Moll, Juergen; Pittala, Valeria; Roletto, Fulvia; Severino, Dino; Soncini, Chiara; Storici, Paola; Tonani, Roberto; Varasi, Mario; Vulpetti, Anna; Vianello, Paola.

inhibition.

Potent and selective Aurora inhibitors identified by the expansion of a Novel scaffold for protein kinase

Journal of Medicinal Chemistry (2005), 48(8), 3080-3084. 13.

Pevarello, Paolo; Bonsignori, Alberto; Dostert, Philippe; Heidempergher, Franco; Pinciroli, Vittorio; Colombo, Maristella; McArthur, Robert A.; Salvati, Patricia; Post, Claes; Fariello, Ruggero G.; Varasi, Mario.

Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives.

Journal of Medicinal Chemistry (1998), 41(4), 579-590. 14.

Heidempergher, Franco; Pillan, Antonio; Pinciroli, Vittorio; Vaghi, Fabrizio; Arrigoni, Claudio; Bolis, Giorgio; Caccia, Carla; Dho, Luciano; McArthur, Robert; Varasi, Mario.

15.

Tagliavini, F.; McArthur, R. A.; Canciani, B.; Giaccone, G.; Porro, M.; Bugiani, M.; Lievens, P. M.-J.; Bugiani, O.; Peri, E.; Dall'Ara, P.; Rocchi, M.; Poli, G.; Forloni, G.; Bandiera, T.; Varasi, M.; Suarato, A.; Cassutti, P.; Cervini, M. A.; Lansen, J.; Salmona, M.; Post, C.

Effectiveness of anthracycline against experimental prion disease in Syrian hamsters.

Science (Washington, D. C.) (1997), 276(5315), 1119-1122.

Congresses

• • • •

Phenylimidazolidin-2-one Derivatives as Selective 5-HT3 Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT3 Receptor Binding.

Journal of Medicinal Chemistry (1997), 40(21), 3369-3380. Member of the Organizing Committee of the European Advanced School of Medicinal Chemistry in Urbino (1995-2011) Elected Member of the Board of the “Divisione di Chimica Farmaceutica-Società Chimica italiana” [2007-2009 and 2010-2012] Member of the Scientific Committee of the National Congress of Medicinal Chemistry (2007 2013) Member of the International Scientific Committee of XXIIIrd International Symposium on Medicinal Chemistry (EFMC-ISMC 2014),