7NZY
Crystal structure of human Casein Kinase I delta in complex with CGS-15943
Summary for 7NZY
| Entry DOI | 10.2210/pdb7nzy/pdb |
| Descriptor | Casein kinase I isoform delta, 9-chloranyl-2-(furan-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine, MALONATE ION, ... (5 entities in total) |
| Functional Keywords | kinase, inhibitor, complex, atp-competitive, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 147762.29 |
| Authors | Pichlo, C.,Baumann, U. (deposition date: 2021-03-24, release date: 2022-10-05, Last modification date: 2024-11-06) |
| Primary citation | Wesseler, F.,Lohmann, S.,Riege, D.,Halver, J.,Roth, A.,Pichlo, C.,Weber, S.,Takamiya, M.,Muller, E.,Ketzel, J.,Flegel, J.,Gihring, A.,Rastegar, S.,Bertrand, J.,Baumann, U.,Knippschild, U.,Peifer, C.,Sievers, S.,Waldmann, H.,Schade, D. Phenotypic Discovery of Triazolo[1,5- c ]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype. J.Med.Chem., 65:15263-15281, 2022 Cited by PubMed Abstract: Phenotypic drug discovery (PDD) continues to fuel the research and development pipelines with first-in-class therapeutic modalities, but success rates critically depend on the quality of the underlying model system. Here, we employed a stem cell-based approach for the target-agnostic, yet pathway-centric discovery of small-molecule cytokine signaling activators to act as morphogens during development and regeneration. Unbiased screening identified triazolo[1,5-]quinazolines as a new-in-class in vitro and in vivo active amplifier of the bone morphogenetic protein (BMP) pathway. Cellular BMP outputs were stimulated via enhanced and sustained availability of BMP-Smad proteins, strictly dependent on a minimal BMP input. Holistic target deconvolution unveiled a unique mechanism of dual targeting of casein kinase 1 and phosphatidyl inositol 3-kinase isoforms as key effectors for efficient amplification of osteogenic BMP signaling. This work underscores the asset of PDD to discover unrecognized polypharmacology signatures, in this case significantly expanding the chemical and druggable space of BMP modulators. PubMed: 36346705DOI: 10.1021/acs.jmedchem.2c01199 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
Download full validation report
