6MOB

Crystal structure of KIT1 in complex with DP2976 via co-crystallization

Summary for 6MOB

• Entry DOI: 10.2210/pdb6mob/pdb
• Descriptor: Mast/stem cell growth factor receptor Kit, NITRATE ION, N-{4-chloro-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl}-N'-phenylurea, ... (4 entities in total)
• Functional Keywords: deciphera, kit1 kinase, dp2976, decode, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 36665.86

Authors

Edwards, T.E.,Abendroth, J.,Safford, K.,Chun, L. (deposition date: 2018-10-04, release date: 2019-07-31, Last modification date: 2024-04-03)

Primary citation

Smith, B.D.,Kaufman, M.D.,Lu, W.P.,Gupta, A.,Leary, C.B.,Wise, S.C.,Rutkoski, T.J.,Ahn, Y.M.,Al-Ani, G.,Bulfer, S.L.,Caldwell, T.M.,Chun, L.,Ensinger, C.L.,Hood, M.M.,McKinley, A.,Patt, W.C.,Ruiz-Soto, R.,Su, Y.,Telikepalli, H.,Town, A.,Turner, B.A.,Vogeti, L.,Vogeti, S.,Yates, K.,Janku, F.,Abdul Razak, A.R.,Rosen, O.,Heinrich, M.C.,Flynn, D.L.
Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
Cancer Cell, 35:738-751.e9, 2019

PubMed Abstract: Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.

PubMed: 31085175
DOI: 10.1016/j.ccell.2019.04.006

Experimental method

X-RAY DIFFRACTION (1.8 Å)