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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Discovery of a Novel MNK Inhibitor (NSP-1047) with In Vivo Anti-acute Myeloid Leukemia Activity
Bing Li1, Shuang Xia2, Ke Zhang1
1Novostar Pharmaceuticals, Ltd., Shanghai 201210, China.
Abstract:
MAPK-interacting kinases (MNKs) phosphorylate the eukaryotic initiation factor 4E (eIF4E), critical for cap-dependent translation. The MNK/eIF4E pathway plays a role in the development and progression of various hematological and solid tumors. Here, we report the discovery of a novel polycyclic compound 21e (NSP-1047), which inhibits MNK1 and MNK2 with high potency, leading to a reduction in the phosphorylation of eIF4E. NSP-1047 shows strong in vitro antiproliferative activity against multiple acute myeloid leukemia (AML) cell lines. Meanwhile, it enhances anticancer immune responses by downregulating the expression of immune checkpoint proteins and suppressing the secretion of inflammatory cytokines. NSP-1047 displays excellent ADME and pharmacokinetic properties, and encouraging safety profiles, with a highest nonsevere toxic dose (HNSTD) of 750 and 200 mg/kg for SD rats and Beagle dogs, respectively. In vivo efficacy evaluation in AML xenografts demonstrates significant tumor suppression, with tumor regression observed at tolerated doses, both as monotherapy and in combination with Ara-C or venetoclax.
Insights
A novel compound, NSP-1047, effectively inhibits MAPK-interacting kinases (MNKs) and reduces eIF4E phosphorylation. This compound demonstrates potent anti-leukemia activity and enhances anti-tumor immune responses in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MAPK-interacting kinases (MNKs) phosphorylate eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation.
- The MNK/eIF4E pathway is implicated in the pathogenesis of various hematological malignancies and solid tumors.
Purpose of the Study:
- To discover and characterize novel inhibitors of MNK1 and MNK2.
- To evaluate the therapeutic potential of a novel compound, NSP-1047, in acute myeloid leukemia (AML).
Main Methods:
- In vitro biochemical assays to assess MNK1/2 inhibition and eIF4E phosphorylation.
- In vitro antiproliferative assays against AML cell lines.
- Assessment of immune modulation, including immune checkpoint protein expression and cytokine secretion.
- Pharmacokinetic and safety profiling in preclinical species.
- In vivo efficacy studies in AML xenograft models, both as monotherapy and in combination therapy.
Main Results:
- NSP-1047 potently inhibits MNK1 and MNK2, reducing eIF4E phosphorylation.
- NSP-1047 exhibits strong in vitro antiproliferative effects against AML cell lines.
- NSP-1047 downregulates immune checkpoint proteins and suppresses inflammatory cytokine secretion, enhancing anti-tumor immunity.
- NSP-1047 demonstrates favorable ADME/pharmacokinetic properties and safety profiles.
- Significant tumor suppression and regression were observed in AML xenografts with NSP-1047 monotherapy and combination therapy.
Conclusions:
- NSP-1047 is a potent dual inhibitor of MNK1/2 with significant preclinical efficacy in AML.
- NSP-1047 exhibits immunomodulatory effects that may contribute to its anti-leukemia activity.
- NSP-1047 represents a promising therapeutic candidate for AML treatment.
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