Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors

Area of Science:

• Oncology
• Pharmacology
• Structural Biology

Background:

• Aurora kinases (A, B, C) are crucial for mitosis and frequently overexpressed in human cancers, making them key targets for chemotherapy.
• Numerous Aurora kinase inhibitors are in clinical development, with most being pan-selective and few targeting specific isoforms (Aurora A or B).
• Despite extensive research, no Aurora kinase inhibitor has yet reached the market.

Purpose of the Study:

• To analyze structural biology and computational aspects of Aurora kinase inhibitor design.
• To explore strategies for developing subtype-selective inhibitors, particularly for Aurora A.
• To identify potential therapeutic advantages of subtype-selective Aurora kinase inhibitors over pan-selective ones.

Main Methods:

• Review of structural biology and computational data for Aurora kinase inhibitors.
• Analysis of isoform-specific residues in the active sites of Aurora kinases.
• Examination of existing pan-selective and subtype-selective Aurora kinase inhibitors.

Main Results:

• Subtype-selective inhibitors may offer improved therapeutic profiles by avoiding Aurora B-mediated neutropenia.
• Targeting specific residues like Leu215, Thr217, and Arg220 in Aurora A, or Arg159, Glu161, and Lys164 in Aurora B, is a viable strategy.
• The Thr217 residue in Aurora A presents a promising target for developing selective inhibitors, as demonstrated by MLN8054.

Conclusions:

• Designing subtype-selective Aurora kinase inhibitors is challenging due to conserved active sites among isoforms.
• Targeting specific amino acid residues offers a rational approach to achieve subtype selectivity.
• Further preclinical and clinical studies of subtype-selective Aurora inhibitors are essential for their potential market approval in cancer treatment.