4HVS

Crystal structure of KIT kinase domain with a small molecule inhibitor, PLX647

4HVS の概要

• エントリーDOI: 10.2210/pdb4hvs/pdb
• 分子名称: Mast/stem cell growth factor receptor Kit, 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-[4-(trifluoromethyl)benzyl]pyridin-2-amine (3 entities in total)
• 機能のキーワード: transferase, tyrosine-protein kinase, atp-binding, kinase-kinase inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane; Single-pass type I membrane protein. Isoform 3: Cytoplasm: P10721
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38424.48

構造登録者

Zhang, Y.,Zhang, C. (登録日: 2012-11-06, 公開日: 2013-03-27, 最終更新日: 2023-09-20)

主引用文献

Zhang, C.,Ibrahim, P.N.,Zhang, J.,Burton, E.A.,Habets, G.,Zhang, Y.,Powell, B.,West, B.L.,Matusow, B.,Tsang, G.,Shellooe, R.,Carias, H.,Nguyen, H.,Marimuthu, A.,Zhang, K.Y.,Oh, A.,Bremer, R.,Hurt, C.R.,Artis, D.R.,Wu, G.,Nespi, M.,Spevak, W.,Lin, P.,Nolop, K.,Hirth, P.,Tesch, G.H.,Bollag, G.
Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.
Proc.Natl.Acad.Sci.USA, 110:5689-5694, 2013

PubMed Abstract: Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.

PubMed: 23493555
DOI: 10.1073/pnas.1219457110

実験手法

X-RAY DIFFRACTION (1.9 Å)