Nemes Zoltán, Takács-Novák Krisztina, Völgyi Gergely, Valko Klara, Béni Szabolcs, Horváth Zoltán, Szokol Bálint, Breza Nóra, Dobos Judit, Szántai-Kis Csaba, Illyés Eszter, Boros Sándor, Kok Robbert Jan, Őrfi László
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.
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre street 9, Budapest H-1092, Hungary.
Bioorg Med Chem Lett. 2018 Aug 1;28(14):2391-2398. doi: 10.1016/j.bmcl.2018.06.026. Epub 2018 Jun 18.
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, pK, 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.
急性髓系白血病（AML）是成人中最常见的白血病类型。舒尼替尼是一种多激酶抑制剂，是首个临床上用于治疗AML的Fms样酪氨酸激酶3（FLT3）抑制剂。脱靶效应是多激酶抑制剂的一个主要问题。由于靶向递送可能减少此类不良副作用，我们的目标是开发舒尼替尼的新型氨基酸取代衍生物，这些衍生物是与抗体和肽缀合使用的有力候选物。在本文中，我们介绍了62种Fms样酪氨酸激酶3-内部串联重复（FLT3-ITD）突变激酶抑制剂的合成、物理化学性质和体外特性，这些抑制剂带有氨基酸部分，适合通过其羧基与基于肽的递送系统缀合。我们测定了这些化合物的溶解度、pK、CHI和LogP值，以及它们对FLT3-ITD突变激酶和MV4-11细胞系的抑制潜力。这些化合物的酯衍生物在亚微摩尔浓度下抑制MV4-11白血病细胞系的生长。
