2. Academic Validation
  3. Hedgehog pathway inhibitors of the acylthiourea and acylguanidine class show antitumor activity on colon cancer in vitro and in vivo

Hedgehog pathway inhibitors of the acylthiourea and acylguanidine class show antitumor activity on colon cancer in vitro and in vivo

  • Eur J Med Chem. 2018 Sep 5:157:368-379. doi: 10.1016/j.ejmech.2018.07.053.
Loredana Vesci 1,  Ferdinando Maria Milazzo 2,  Maria Antonietta Stasi 3,  Silvia Pace 4,  Francesco Manera 5,  Carlo Tallarico 6,  Elena Cini 7,  Elena Petricci 8,  Fabrizio Manetti 9,  Rita De Santis 10,  Giuseppe Giannini 11
Affiliations

Affiliations

  • 1 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: loredana.vesci@alfasigma.com.
  • 2 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: ferdinando.milazzo@alfasigma.com.
  • 3 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: mariaantonietta.stasi@alfasigma.com.
  • 4 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: silvia.pace@alfasigma.com.
  • 5 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: francesco.manera@alfasigma.com.
  • 6 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: carlo.tallarico@alfasigma.com.
  • 7 Lead Discovery Siena Srl, via Fiorentina 1, I-53100, Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Dipartimento di Eccellenza 2018-2022, via A. Moro 2, I-53100, Siena, Italy. Electronic address: cinielena@libero.it.
  • 8 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Dipartimento di Eccellenza 2018-2022, via A. Moro 2, I-53100, Siena, Italy. Electronic address: elena.petricci@unisi.it.
  • 9 Lead Discovery Siena Srl, via Fiorentina 1, I-53100, Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Dipartimento di Eccellenza 2018-2022, via A. Moro 2, I-53100, Siena, Italy. Electronic address: fabrizio.manetti@unisi.it.
  • 10 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: rita.desantis@alfasigma.com.
  • 11 Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: giuseppe.giannini@alfasigma.com.
PMID: 30099257 DOI: 10.1016/j.ejmech.2018.07.053
Abstract

Small series of acylguanidine and acylthiourea derivatives were synthesized in gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon Cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized to further development with the perspective of clinical studies.

Keywords

ADME-Tox; Acylguanidine; Gram-scale synthesis; Hedgehog inhibitor; In vivo pharmacokinetics; LS180 xenograft.

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