6P5P
Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Anti-Tumor Agent
Summary for 6P5P
| Entry DOI | 10.2210/pdb6p5p/pdb |
| Descriptor | Rho-associated protein kinase 2, 2-[(2S)-1-azabicyclo[2.2.2]octan-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (2 entities in total) |
| Functional Keywords | kinase, inhibitor, oral, anti-tumor, transferase-transferase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 186235.66 |
| Authors | Hoffman, I.D.,Skene, R.J. (deposition date: 2019-05-30, release date: 2020-01-15, Last modification date: 2023-10-11) |
| Primary citation | Kurasawa, O.,Miyazaki, T.,Homma, M.,Oguro, Y.,Imada, T.,Uchiyama, N.,Iwai, K.,Yamamoto, Y.,Ohori, M.,Hara, H.,Sugimoto, H.,Iwata, K.,Skene, R.,Hoffman, I.,Ohashi, A.,Nomura, T.,Cho, N. Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent. J.Med.Chem., 63:1084-1104, 2020 Cited by PubMed Abstract: In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-]pyrimidinone analogue showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound , which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of , which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound () possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented. PubMed: 31895562DOI: 10.1021/acs.jmedchem.9b01427 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.3 Å) |
Structure validation
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