5WR7

Crystal structure of Trk-A complexed with a selective inhibitor CH7057288

Summary for 5WR7

• Entry DOI: 10.2210/pdb5wr7/pdb
• Descriptor: High affinity nerve growth factor receptor, N-tert-butyl-2-[2-[6,6-dimethyl-8-(methylsulfonylamino)-11-oxidanylidene-naphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methyl-pyridine-4-carboxamide (3 entities in total)
• Functional Keywords: trk-a, kinase domain, high affinity nerve growth factor receptor, proteros biostructures gmbh, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35315.63

Authors

Tanaka, H.,Blaesse, M.,Augustin, M.,Goesser, C. (deposition date: 2016-11-30, release date: 2017-12-06, Last modification date: 2024-11-20)

Primary citation

Tanaka, H.,Sase, H.,Tsukaguchi, T.,Hasegawa, M.,Tanimura, H.,Yoshida, M.,Sakata, K.,Fujii, T.,Tachibana, Y.,Takanashi, K.,Higashida, A.,Hasegawa, K.,Ono, Y.,Oikawa, N.,Mio, T.
Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer.
Mol. Cancer Ther., 17:2519-2529, 2018

PubMed Abstract: Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of and activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.

PubMed: 30242093
DOI: 10.1158/1535-7163.MCT-17-1180

Experimental method

X-RAY DIFFRACTION (2.76 Å)