8C0F

Tubulin-PTC596 complex

8C0F の概要

• エントリーDOI: 10.2210/pdb8c0f/pdb
• 分子名称: Tubulin alpha-1B chain, GLYCEROL, 5-fluoranyl-2-(6-fluoranyl-2-methyl-benzimidazol-1-yl)-~{N}4-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine, ... (15 entities in total)
• 機能のキーワード: cell cycle, tubulin fold, cytoskeleton, microtubule
• 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: 265478.17

構造登録者

Prota, A.E.,Muehlethaler, T.,Weetall, M.,Steinmetz, M.O. (登録日: 2022-12-16, 公開日: 2022-12-28, 最終更新日: 2024-02-07)

主引用文献

Jernigan, F.,Branstrom, A.,Baird, J.D.,Cao, L.,Dali, M.,Furia, B.,Kim, M.J.,O'Keefe, K.,Kong, R.,Laskin, O.L.,Colacino, J.M.,Pykett, M.,Mollin, A.,Sheedy, J.,Dumble, M.,Moon, Y.-C.,Sheridan, R.,Muehlethaler, T.,Spiegel, R.J.,Prota, A.E.,Steinmetz, M.O.,Weetall, M.
Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent
Mol Cancer Ther, 20:1846-1857, 2021

PubMed Abstract: PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Using X-ray crystallography, it was determined that PTC596 binds to the colchicine site of tubulin with unique key interactions. PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations in mouse models of leiomyosarcomas and glioblastoma. PTC596 demonstrated efficacy in an orthotopic model of glioblastoma under conditions where temozolomide was inactive. In a first-in-human phase I clinical trial in patients with cancer, PTC596 monotherapy drug exposures were compared with those predicted to be efficacious based on mouse models. PTC596 is currently being tested in combination with dacarbazine in a clinical trial in adults with leiomyosarcoma and in combination with radiation in a clinical trial in children with diffuse intrinsic pontine glioma.

PubMed: 34315764
DOI: 10.1158/1535-7163.MCT-20-0774

実験手法

X-RAY DIFFRACTION (2.1005 Å)