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

Nemes, Zoltán; Takács‐Novák, Krisztina; Völgyi, Gergely; Valkó, Klára; Béni, Szabolcs; Horváth, Zoltán; Szokol, Bálint; Breza, Nóra; Dobos, Judit; Szántai-Kis, Csaba; Illyés, Eszter; Boros, Sándor; Kok, Robbert J.; Őrfi, László

doi:10.1016/j.bmcl.2018.06.026

Cited by 7 publications

(3 citation statements)

References 20 publications

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“…Novel amino-acid-substituted sunitinib analogues released active compound candidates have been developed in order to improve selectivity towards FLT3 [ 61 ]. Among them, the mono-carboxylic acid compound 20a provided the best results in terms of affinity against FLT3-ITD and activity against MV4-11 cells.…”

Section: Novel Molecules Targeting Proliferative Mechanisms In Acute ...mentioning

confidence: 99%

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

et al. 2023

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Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kd, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

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Section: Novel Molecules Targeting Proliferative Mechanisms In Acute ...mentioning

confidence: 99%

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

et al. 2023

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“…Recently in 2018, Nemes et al reported the phenyl methoxy ester Sunitinib derivative compound 13 , through western blotting assay, can exhibit fundamental inhibitory activity versus FLT3-ITD at a dosage of 1.25 μM compared with reference Sunitinib with inhibition percentages of 90.9%, and 92.3%, respectively ( Table 3 ) [ 83 ]. Additionally, this compound displayed a promising antiproliferative activity against MV4-11 acute myeloid cells with IC 50 equal to 2.2 μM.…”

Section: Oxindole Based Flt3 Inhibitorsmentioning

confidence: 99%

Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia

et al. 2023

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Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients. These mutations are accompanied by poor clinical response, although all these progressions in identifying and interpreting biological AML bio-targets. Several small structured FLT3 inhibitors have been ameliorated to struggle against AML. Despite all these developments regarding these inhibitors, the Overall survival rate is about five years or more in less than one-third of diagnosed AML patients. Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan. Interestingly, indole-based motifs had risen as advantaged scaffolds with unusual multiple kinase inhibitory activity. This review summarises indole-based FLT3 inhibitors and related scaffolds, including FDA-approved drugs, clinical candidates, and other bioactive compounds. Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.

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“…It is noticeable that off-target effects extensively exist in multikinase inhibitors in the field of cancer treatment. − To overcome such undesired side effects, 62 sunitinib derivatives containing amino acid substituents were designed, synthesized, and depicted based on targeted delivery strategies . In all of these prepared compounds, Őrfi-20a , bearing the amino acid moiety, displayed high affinity against FLT3-ITD mutant kinases, preferential cellular activity (MV4-11), and high log D at pH = 5.5, which was considered as a promising candidate to be conjugated with antibodies and peptides via its carboxyl group (Figure c).…”

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

et al. 2020

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Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.

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

Cited by 7 publications

References 20 publications

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

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