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

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.

• Authors: Zoltán Nemes, Krisztina Takács-Novák, Gergely Völgyi, Klara Valko, Szabolcs Béni, Zoltán Horváth, Bálint Szokol, Nóra Breza, Judit Dobos, Csaba Szántai-Kis, Eszter Illyés, Sándor Boros, Robbert Jan Kok, László Őrfi
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 14 Pg. 2391-2398 (08 01 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 29935772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Amino Acids
• Antineoplastic Agents
• Protein Kinase Inhibitors
• fms-Like Tyrosine Kinase 3
• Sunitinib

Topics

• Amino Acids (chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Solubility
• Structure-Activity Relationship
• Sunitinib (chemical synthesis, chemistry, pharmacology)
• Tandem Repeat Sequences (drug effects)
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, metabolism)