6KLA

Crystal structure of human c-KIT kinase domain in complex with compound 15a

Summary for 6KLA

• Entry DOI: 10.2210/pdb6kla/pdb
• Descriptor: Mast/stem cell growth factor receptor Kit, N-[6-(4-ethylpiperazin-1-yl)-2-methyl-pyrimidin-4-yl]-5-pyridin-4-yl-1,3-thiazol-2-amine (3 entities in total)
• Functional Keywords: tyrosine kinase inhibitor, kinase phosphorylation, atp competitor, transmembrane receptor protein, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 38051.06

Authors

Wu, T.S.,Peng, Y.H.,Hsueh, C.C.,Wu, S.Y. (deposition date: 2019-07-30, release date: 2019-11-27, Last modification date: 2023-11-22)

Primary citation

Lin, W.H.,Wu, S.Y.,Yeh, T.K.,Chen, C.T.,Song, J.S.,Shiao, H.Y.,Kuo, C.C.,Hsu, T.,Lu, C.T.,Wang, P.C.,Wu, T.S.,Peng, Y.H.,Lin, H.Y.,Chen, C.P.,Weng, Y.L.,Kung, F.C.,Wu, M.H.,Su, Y.C.,Huang, K.W.,Chou, L.H.,Hsueh, C.C.,Yen, K.J.,Kuo, P.C.,Huang, C.L.,Chen, L.T.,Shih, C.,Tsai, H.J.,Jiaang, W.T.
Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.
J.Med.Chem., 62:11135-11150, 2019

PubMed Abstract: Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound , with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that may be a potential anticancer drug for the treatment of GISTs and AML.

PubMed: 31721578
DOI: 10.1021/acs.jmedchem.9b01229

Experimental method

X-RAY DIFFRACTION (2.109 Å)