9YMG

Human KIF18A-DARPin fusion protein bound to AMP-PNP and tubulin

Summary for 9YMG

• Entry DOI: 10.2210/pdb9ymg/pdb
• Descriptor: Tubulin alpha-1B chain, Tubulin beta chain, Kinesin-like protein KIF18A, DARPin fusion protein, ... (9 entities in total)
• Functional Keywords: kinesin, motor protein, microtubule, complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 322688.03

Authors

Lockbaum, G.J.,Lee, Y.-T.,Boriack-Sjodin, P.A.,Grigoriu, S. (deposition date: 2025-10-09, release date: 2025-11-05, Last modification date: 2025-12-03)

Primary citation

Sparling, B.A.,Lee, H.,Zablocki, M.M.,Lynes, M.M.,Grigoriu, S.,Shehaj, L.,Lockbaum, G.J.,Khan, S.K.,Hotz, T.,Lee, Y.T.,Buker, S.M.,Gotur, D.,Lu, C.,Ribich, S.,Blakemore, S.J.,Boriack-Sjodin, P.A.,Silver, S.J.,Copeland, R.A.,Duncan, K.W.
Discovery of Kinesin KIF18A Inhibitor ATX020: Tactical Application of Silicon Atom Replacement.
Acs Med.Chem.Lett., 16:2309-2319, 2025

PubMed Abstract: KIF18A is an ATP-dependent, plus end-directed mitotic kinesin that facilitates chromosome alignment and spindle microtubule dynamics during mitosis. Certain cancer types may be particularly vulnerable to KIF18A inhibition, specifically cancer cells with high levels of chromosomal instability (CIN). As part of efforts to identify KIF18A inhibitors, silicon atom replacement was explored to improve ligand-KIF18A interactions and ADME parameters. This tactic resulted in the discovery of a series of silapiperidine-containing KIF18A inhibitors and culminated in the identification and characterization of . is a potent KIF18A inhibitor with a high degree of kinesin selectivity, favorable and ADME properties, and robust efficacy in the OVCAR-3 cell-derived xenograft (CDX) model. A high-resolution crystal structure of the KIF18A-tubulin complex and an experimentally guided model of bound to the complex are provided, supporting future structure-based drug design of KIF18A inhibitors.

PubMed: 41257005
DOI: 10.1021/acsmedchemlett.5c00512

Experimental method

X-RAY DIFFRACTION (2.406 Å)