2. Academic Validation
  3. Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML

Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML

  • Bioorg Med Chem Lett. 2018 Aug 1;28(14):2391-2398. doi: 10.1016/j.bmcl.2018.06.026.
Zoltán Nemes 1,  Krisztina Takács-Novák 2,  Gergely Völgyi 2,  Klara Valko 3,  Szabolcs Béni 4,  Zoltán Horváth 5,  Bálint Szokol 5,  Nóra Breza 5,  Judit Dobos 5,  Csaba Szántai-Kis 5,  Eszter Illyés 5,  Sándor Boros 5,  Robbert Jan Kok 6,  László Őrfi 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre street 9, Budapest H-1092, Hungary; Vichem Chemie Ltd, Herman Ottó street 15, Budapest H-1022, Hungary.
  • 2 Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre street 9, Budapest H-1092, Hungary.
  • 3 Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
  • 4 Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre street 9, Budapest H-1092, Hungary; Department of Pharmacognosy, Semmelweis University, Üllői street 26, Budapest H-1085, Hungary.
  • 5 Vichem Chemie Ltd, Herman Ottó street 15, Budapest H-1022, Hungary.
  • 6 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, Utrecht 3584 CG, The Netherlands.
  • 7 Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre street 9, Budapest H-1092, Hungary; Vichem Chemie Ltd, Herman Ottó street 15, Budapest H-1022, Hungary. Electronic address: orfi.laszlo@pharma.semmelweis-univ.hu.
PMID: 29935772 DOI: 10.1016/j.bmcl.2018.06.026
Abstract

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Sunitinib, a multikinase inhibitor, was the first Fms-like tyrosine kinase 3 (FLT3) inhibitor clinically used against AML. Off-target effects are a major concern for multikinase inhibitors. As targeted delivery may reduce such undesired side effects, our goal was to develop novel amino acid substituted derivatives of sunitinib which are potent candidates to be used conjugated with Antibodies and Peptides. In the current paper we present the synthesis, physicochemical and in vitro characterization of sixty two Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant kinase inhibitors, bearing amino acid moieties, fit to be conjugated with peptide-based delivery systems via their carboxyl group. We determined the solubility, pKa, CHI and LogP values of the compounds along with their inhibition potential against FLT3-ITD mutant kinase and on MV4-11 cell line. The ester derivatives of the compounds inhibit the growth of the MV4-11 leukemia cell line at submicromolar concentration.

Keywords

Acute myeloid leukemia; Chromatographic Hydrophobicity Index; FLT3-ITD kinase inhibitior; Peptide based targeted delivery; Shake-flask partition coefficient determination.

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