9U6D

Crystal structure of tubulin-RB3-TTL in complex with X8

This is a non-PDB format compatible entry.

Summary for 9U6D

• Entry DOI: 10.2210/pdb9u6d/pdb
• Descriptor: Tubulin alpha-1B chain, 2-[2-fluoranyl-4-[4-[2-[4-[(1~{R},2~{S})-2-fluoranylcyclopropyl]carbonylpiperazin-1-yl]ethoxy]phenyl]phenyl]-~{N}-(phenylmethyl)ethanamide, Tubulin beta chain, ... (11 entities in total)
• Functional Keywords: tubulin, cell cycle
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 267068.48

Authors

Yan, W.,Yang, J.H. (deposition date: 2025-03-23, release date: 2026-03-25, Last modification date: 2026-06-24)

Primary citation

Zhang, C.,Wang, Y.,Gao, C.,Sun, M.,Tang, M.,Wang, F.,Chen, H.,Zhang, S.,Liu, L.,Li, Q.,Cui, X.,Hu, X.,Yang, Z.,Yang, J.,Li, Y.
Structure-based design and synthesis of KX-01 analogs as potent antitumor agents targeting the tubulin colchicine binding site.
Eur.J.Med.Chem., 312:118849-118849, 2026

PubMed Abstract: Our preliminary studies indicated that KX-01 inhibits tubulin polymerization in a reversible and concentration-dependent manner, resulting in dramatically low toxicity across various solid and liquid tumor types. However, KX-01 has not yet been approved as an anticancer agent due to its insufficient efficacy, and research on its derivatives remains limited. To improve its antitumor activity and investigate the structure-activity relationships (SARs), sixty-seven KX-01 analogs were designed and synthesized based on the KX-01-tubulin cocrystal structure. Among them, compound 8h exhibited the most potent antiproliferative activity, with IC values of 3.5 ± 0.6, 2.4 ± 0.2, 15.7 ± 3.1, 22.1 ± 1.9, and 7.3 ± 1.1 nM against HCT116, HeLa, A2780S, A2780T, and HT29 cells, respectively, indicating its potential to overcome multidrug resistance. Replacing the endocyclic nitrogen atom in the pyridine ring of KX-01 with an exocyclic fluorine atom directly results in the loss of Src inhibitory activity. The cocrystal of 8h-tubulin complex revealed that it simultaneously occupies the colchicine site in β-tubulin and a cavity in α-tubulin. In the HT29 xenograft model, orally administered 8h (5 mg/kg, once daily) showed marginally superior in vivo antitumor efficacy than KX-01.

PubMed: 42001543
DOI: 10.1016/j.ejmech.2026.118849

Experimental method

X-RAY DIFFRACTION (2.54 Å)