9U9Q

Tubulin-RB3-TTL in complex with C38

This is a non-PDB format compatible entry.

Summary for 9U9Q

• Entry DOI: 10.2210/pdb9u9q/pdb
• Descriptor: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: tubulin, cell cycle
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 267788.40

Authors

Yan, W.,Yang, J.H. (deposition date: 2025-03-29, release date: 2026-04-01, Last modification date: 2026-06-24)

Primary citation

Zhang, C.,Yan, W.,Chen, H.,Sun, M.,Wang, F.,Wang, Y.,Zhang, S.,Liu, L.,Li, Q.,Hu, X.,Yang, Z.,Yang, J.,Li, Y.
Structure-based design and synthesis of 3-substituted-1,2,4-triazolo[1,5-a]pyrimidines as dual vinca/gatorbulin-site ligands for cancer treatment.
Eur.J.Med.Chem., 301:118245-118245, 2026

PubMed Abstract: Our preliminary studies indicate that cevipabulin concurrently binds to both the vinca site and the gatorbulin site, and promotes tubulin degradation. To improve its antiproliferative activity and investigate the structure-activity relationships (SARs), thirty-eight cevipabulin derivatives were designed and synthesized based on the cevipabulin-tubulin cocrystal structure. Among them, compound 8g exerted optimal antiproliferative activity, with IC values ranging from 0.016 to 0.035 μM against three tested tumor cell lines. The cocrystal structure of the 8g-tubulin complex revealed that it simultaneously occupies both the vinca site and the gatorbulin site, while maintaining a binding mode similar to that of cevipabulin. Furthermore, 8g promoted αβ-tubulin degradation and displayed good oral bioavailability. In an HT29 xenograft model, oral administration of 8g at doses of 20 and 40 mg/kg every 3 days resulted in potent in vivo antitumor activity, with tumor growth inhibition (TGI) rates of 41.0 % and 49.5 %, respectively. Moreover, 8g exhibited significantly reduced toxicity and fewer adverse effects compared to cevipabulin, supporting its potential as a promising therapeutic agent for cancer treatment.

PubMed: 41106064
DOI: 10.1016/j.ejmech.2025.118245

Experimental method

X-RAY DIFFRACTION (2.93 Å)