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
  • 1. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 2. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 3. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 4. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 5. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 6. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 10. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
  • 11. Research & Development, Alfasigma SpA, via Pontina, Km 30.400, I-00040, Pomezia, Italy. Electronic address: [email protected].
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.