2. Academic Validation
  3. Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma

Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma

  • Eur J Med Chem. 2021 Nov 5:223:113653. doi: 10.1016/j.ejmech.2021.113653.
Enrico Rango 1,  Lucia D'Antona 2,  Giulia Iovenitti 1,  Annalaura Brai 1,  Arianna Mancini 1,  Claudio Zamperini 3,  Claudia Immacolata Trivisani 1,  Stefano Marianelli 1,  Anna Lucia Fallacara 1,  Alessio Molinari 1,  Annarita Cianciusi 4,  Silvia Schenone 4,  Nicola Perrotti 5,  Elena Dreassi 6,  Maurizio Botta 7
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
  • 2 Dipartimento di Scienze della Salute, Università"Magna Graecia" di Catanzaro, Viale Europa, 88100, Catanzaro, Italy.
  • 3 Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Siena, Italy.
  • 4 Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, Genoa, 16132, Italy.
  • 5 Dipartimento di Scienze della Salute, Università"Magna Graecia" di Catanzaro, Viale Europa, 88100, Catanzaro, Italy. Electronic address: perrotti@unicz.it.
  • 6 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy. Electronic address: elena.dreassi@unisi.it.
  • 7 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA, 19122, United States.
PMID: 34161866 DOI: 10.1016/j.ejmech.2021.113653
Abstract

Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an Anticancer agent due to its potent Anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of in vitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against SGK1 was evaluated and in vitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant Cancer.

Keywords

ADME; HCC; Kinase inhibitors; Ovarian carcinoma; Pharmacokinetic; Plasmin-activated prodrugs; Prodrugs; Sgk1; Targeted therapy.

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