9BHI

Crystal structure of the MerTK kinase domain with SA4488

これはPDB形式変換不可エントリーです。

9BHI の概要

• エントリーDOI: 10.2210/pdb9bhi/pdb
• 分子名称: Mer tyrosine kinase domain, (5P)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-{(1R,2S)-2-[(4'-{2-[4-(2-oxoethyl)piperazin-1-yl]propan-2-yl}[1,1'-biphenyl]-4-yl)methoxy]cyclopentyl}pyridine-3-carboxamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: receptor tyrosine kinase, atp competitive inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38113.72

構造登録者

Jakob, C.G.,Qui, W.,Jain, R. (登録日: 2024-04-20, 公開日: 2024-10-09, 最終更新日: 2024-10-23)

主引用文献

Yu, Y.,Jang, M.,Miyashiro, J.,Clark, R.F.,Zhu, G.D.,Gong, J.,Dai, Y.,Frey, R.R.,Penning, T.D.,Kim, H.,Lee, H.K.,Kim, J.K.,Ryu, K.M.,Park, S.J.,Yoon, T.,Li, T.,Kurnick, M.D.,Kapecki, N.J.,Li, L.,Gorman, J.V.,Montgomery, D.A.,Manaves, V.,Bromberg, K.D.,Doktor, S.Z.,Thakur, A.,Wang, J.,Smith, H.A.,Buchanan, F.G.,Ferguson, D.C.,Torrent, M.,Jakob, C.G.,Qiu, W.,Upadhyay, A.K.,Martin, R.L.,Lai, A.,Michaelides, M.R.
Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.
J.Med.Chem., 67:17000-17032, 2024

PubMed Abstract: TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

PubMed: 39283694
DOI: 10.1021/acs.jmedchem.4c01450

実験手法

X-RAY DIFFRACTION (2.07 Å)