8UAK
Crystal structure of the catalytic domain of human PKC alpha (D463N, V568I, S657E) in complex with Darovasertib (NVP-LXS196) at 2.82-A resolution
Summary for 8UAK
| Entry DOI | 10.2210/pdb8uak/pdb |
| Related | 8u37 |
| Descriptor | Protein kinase C alpha type, (6M)-3-amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide (3 entities in total) |
| Functional Keywords | inhibitor, complex, darovasertib, nvp-lxs196, nvp-cjl037, 8u37, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41153.88 |
| Authors | Romanowski, M.J.,Lam, J.,Visser, M. (deposition date: 2023-09-21, release date: 2024-01-24, Last modification date: 2024-11-13) |
| Primary citation | 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 Cited by 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: 38198520DOI: 10.1021/acs.jmedchem.3c02002 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.82 Å) |
Structure validation
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