8U37

Crystal structure of the catalytic domain of human PKC alpha (D463N, V568I, S657E) in complex with NVP-CJL037 at 2.48-A resolution

8U37 の概要

• エントリーDOI: 10.2210/pdb8u37/pdb
• 関連するPDBエントリー: 8uak
• 分子名称: Protein kinase C alpha type, (6M)-3-amino-N-{4-[(3R,4S)-4-amino-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-[3-(trifluoromethoxy)pyridin-2-yl]pyrazine-2-carboxamide, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: transferase-inhibitor complex, transferase/inhibitor
• 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: 41210.18

構造登録者

Romanowski, M.J.,Lam, J.,Visser, M. (登録日: 2023-09-07, 公開日: 2024-01-24, 最終更新日: 2024-11-06)

主引用文献

Visser, M.,Papillon, J.P.N.,Luzzio, M.,LaMarche, M.J.,Fan, J.,Michael, W.,Wang, D.,Zhang, A.,Straub, C.,Mathieu, S.,Kato, M.,Palermo, M.,Chen, C.,Ramsey, T.,Joud, C.,Barrett, R.,Vattay, A.,Guo, R.,Bric, A.,Chung, F.,Liang, G.,Romanowski, M.J.,Lam, J.,Thohan, S.,Atassi, F.,Wylie, A.,Cooke, V.G.
Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.
J.Med.Chem., 67:1447-1459, 2024

PubMed Abstract: Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).

PubMed: 38198520
DOI: 10.1021/acs.jmedchem.3c02002

実験手法

X-RAY DIFFRACTION (2.48 Å)