Discovery of a potent and highly selective transforming growth factor β receptor-associated kinase 1 (TAK1) inhibitor by structure based drug design (SBDD) was written by Muraoka, Terushige;Ide, Mitsuaki;Morikami, Kenji;Irie, Machiko;Nakamura, Mitsuaki;Miura, Takaaki;Kamikawa, Takayuki;Nishihara, Masamichi;Kashiwagi, Hirotaka. And the article was included in Bioorganic & Medicinal Chemistry in 2016.Product Details of 175137-21-0 This article mentions the following:
A novel thienopyrimidinone analog was discovered as a potent and highly selective TAK1 inhibitor using the SBDD approach. TAK1 plays a key role in inflammatory and immune signaling, so TAK1 is considered to be an attractive mol. target for the treatment of human diseases (inflammatory disease, cancer, etc.). After the hit compound had been obtained, the authors’ modifications successfully increased TAK1 inhibitory activity and solubility, but metabolic stability was still unsatisfactory. To improve metabolic stability, the authors conducted metabolic identification. Although the obtained metabolite was fortunately a potent TAK1 inhibitor, its kinase selectivity was low. Subsequently, to achieve high kinase selectivity, the authors used SBDD to follow two strategies: one targeting unique amino acid residues in TAK1, especially the combination of Ser 111 and Asn 114; the other decreasing the interaction with Tyr 106 at the hinge position in TAK1. As expected, the authors’ designed compound (I) showed an excellent kinase selectivity profile in both an inhouse and a com. available panel assay of over 420 kinases and also retained its potent TAK1 inhibitory activity (TAK1 IC50 = 11 nM). In the experiment, the researchers used many compounds, for example, 4-Chloro-7-methylthieno[3,2-d]pyrimidine (cas: 175137-21-0Product Details of 175137-21-0).
4-Chloro-7-methylthieno[3,2-d]pyrimidine (cas: 175137-21-0) belongs to pyrimidine derivatives. Pyrimidines are isomeric with two other forms of diazines: pyridazine, with the nitrogen atoms in the 1 and 2 positions; and pyrazine, with the nitrogen atoms in the 1 and 4 positions. Drugs having the pyrimidine motif have manifested to exhibit gratifying biological activity like anticancer, antiviral, anti-inflammatory, antibacterial, and antihypertensive activities.Product Details of 175137-21-0
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia