First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Acute myeloid leukemia (AML) with NRAS mutations presents a therapeutic challenge.
• GNF-7, a dual inhibitor of ACK1 and GCK, offers a potential strategy for NRAS-mutant AML.
• Structure-activity relationship (SAR) studies are crucial for optimizing drug candidates.

Purpose of the Study:

• To design and identify novel dual inhibitors of ACK1 and GCK targeting NRAS-mutant AML.
• To evaluate the potency, cellular activity, and pharmacokinetic profiles of new GNF-7 derivatives.
• To assess the therapeutic efficacy and toxicity of lead compounds in preclinical models.

Main Methods:

• Synthesis and SAR analysis of GNF-7 derivatives.
• In vitro kinase inhibition assays against ACK1 and GCK.
• Cell proliferation assays in NRAS-mutant AML cell lines.
• Apoptosis and AKT/mTOR signaling pathway analysis.
• In vivo pharmacokinetic studies and efficacy assessments in mouse models (Ba/F3-NRAS-G12D and OCI-AML3 xenografts).

Main Results:

• Compounds 10d, 10g, and 11i demonstrated potent single-digit nanomolar inhibition of ACK1 and GCK.
• These compounds effectively suppressed proliferation of NRAS-mutant AML cells via apoptosis induction and AKT/mTOR pathway blockade.
• Compound 11i exhibited superior kinase and cellular activity, along with improved differential cytotoxicity compared to GNF-7.
• Compound 10k showed favorable pharmacokinetics in mice, prolonged survival in a Ba/F3-NRAS-G12D model, and delayed tumor growth in an OCI-AML3 xenograft model with reduced toxicity.

Conclusions:

• Novel ACK1 and GCK dual inhibitors, particularly 11i and 10k, are potent against NRAS-mutant AML.
• These compounds demonstrate promising therapeutic potential by inhibiting key signaling pathways and exhibiting favorable preclinical profiles.
• The findings provide a strong foundation for the development of new targeted therapies for NRAS-mutant AML.