Discovery of Kinesin KIF18A Inhibitor ATX020: Tactical Application of Silicon Atom Replacement

Area of Science:

• Molecular Biology
• Biochemistry
• Drug Discovery

Background:

• Kinesin motor protein KIF18A is crucial for chromosome alignment and spindle dynamics during mitosis.
• Cancer cells with high chromosomal instability (CIN) are potentially vulnerable to KIF18A inhibition.
• Developing selective KIF18A inhibitors is a therapeutic strategy for certain cancers.

Purpose of the Study:

• To identify novel KIF18A inhibitors using silicon atom replacement strategies.
• To characterize the novel inhibitor ATX020 for its potency, selectivity, and drug-like properties.
• To provide structural insights into KIF18A inhibition for future drug design.

Main Methods:

• Exploration of silicon atom replacement in KIF18A inhibitor design.
• Synthesis and characterization of silapiperidine-containing compounds.
• In vitro and in vivo ADME profiling of ATX020.
• Efficacy testing in an OVCAR-3 cell-derived xenograft (CDX) model.
• High-resolution crystal structure determination of KIF18A-tubulin complex.

Main Results:

• Discovery of a series of silapiperidine-based KIF18A inhibitors.
• Identification of ATX020 as a potent and selective KIF18A inhibitor.
• ATX020 demonstrated favorable in vitro and in vivo ADME properties.
• ATX020 showed robust efficacy in a preclinical cancer model (OVCAR-3 CDX).
• Structural data of KIF18A-tubulin complex with ATX020 was obtained.

Conclusions:

• Silicon atom replacement is an effective strategy for developing KIF18A inhibitors.
• ATX020 is a promising KIF18A inhibitor candidate with potential for cancer therapy.
• Structural information supports further structure-based drug design for KIF18A inhibitors.