Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Nucleophosmin (NPM) is crucial for ribosome assembly and cellular balance.
• NPM C-terminal domain mutations are linked to acute myeloid leukemia (AML) pathogenesis due to impaired folding and localization.
• Developing strategies to stabilize NPM is essential for AML treatment.

Purpose of the Study:

• To identify small molecules that stabilize the C-terminal domain of NPM.
• To investigate the potential of these compounds as pharmacological chaperones for AML therapy.

Main Methods:

• High-throughput screening for compounds that enhance thermal stability of NPM.
• Computational pocket identification and molecular docking to elucidate binding mechanisms.
• Assessing the effect of hit compounds on the folding and nucleolar localization of AML-associated NPM mutants.

Main Results:

• Three hit compounds were identified, increasing the thermal stability of both NPM domains.
• The lead compound promoted folding of an AML-associated NPM mutant.
• Two compounds partially restored nucleolar localization and reduced aggregation of misfolded NPM mutants.
• Molecular docking suggested stabilization via hydrophobic and polar interactions within NPM.

Conclusions:

• The identified compounds exhibit chaperoning potential by stabilizing NPM.
• These compounds represent promising candidates for pharmacological chaperone-based therapies for AML.
• Targeting NPM conformational stability offers a novel therapeutic avenue for AML.