7ZYW

Crystal structure of T2R-TTL-PM534 complex

7ZYW の概要

• エントリーDOI: 10.2210/pdb7zyw/pdb
• 分子名称: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (15 entities in total)
• 機能のキーワード: tubulin, microtubule destabilizing agents, inhibitor, cell cycle/inhibitor, cell cycle-inhibitor complex
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 271088.10

構造登録者

Oliva, M.A.,Diaz, J.F.,Cuevas, C. (登録日: 2022-05-25, 公開日: 2023-11-29, 最終更新日: 2024-06-12)

主引用文献

Lucena-Agell, D.,Guillen, M.J.,Matesanz, R.,Alvarez-Bernad, B.,Hortiguela, R.,Aviles, P.,Martinez-Diez, M.,Santamaria-Nunez, G.,Contreras, J.,Plaza-Menacho, I.,Gimenez-Abian, J.F.,Oliva, M.A.,Cuevas, C.,Diaz, J.F.
PM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.
J.Med.Chem., 67:2619-2630, 2024

PubMed Abstract: Targeting microtubules is the most effective wide-spectrum pharmacological strategy in antitumoral chemotherapy, and current research focuses on reducing main drawbacks: neurotoxicity and resistance. PM534 is a novel synthetic compound derived from the Structure-Activity-Relationship study on the natural molecule PM742, isolated from the sponge of the , family , genus (du Bocage 1869). PM534 targets the entire colchicine binding domain of tubulin, covering four of the five centers of the pharmacophore model. Its nanomolar affinity and high retention time modulate a strikingly high antitumor activity that efficiently overrides two resistance mechanisms in cells (detoxification pumps and tubulin βIII isotype overexpression). Furthermore, PM534 induces significant inhibition of tumor growth in mouse xenograft models of human non-small cell lung cancer. Our results present PM534, a highly effective new compound in the preclinical evaluation that is currently in its first human Phase I clinical trial.

PubMed: 38294341
DOI: 10.1021/acs.jmedchem.3c01775

実験手法

X-RAY DIFFRACTION (2.45 Å)