8c0f

Tubulin-PTC596 complex

spinqualitylabelsall models 8c0f, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8c0f is a 6 chain structure with sequence from Bos taurus, Gallus gallus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACP, CA, EDO, GDP, GOL, GTP, IMD, MES, MG, SOZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TBA1B_BOVIN Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. Publication Abstract from PubMed 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 in vitro 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. Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent.,Jernigan F, Branstrom A, Baird JD, Cao L, Dali M, Furia B, Kim MJ, O'Keefe K, Kong R, Laskin OL, Colacino JM, Pykett M, Mollin A, Sheedy J, Dumble M, Moon YC, Sheridan R, Muhlethaler T, Spiegel RJ, Prota AE, Steinmetz MO, Weetall M Mol Cancer Ther. 2021 Oct;20(10):1846-1857. doi: 10.1158/1535-7163.MCT-20-0774. , Epub 2021 Jul 26. PMID:34315764 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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