59871-14-6Relevant articles and documents
Structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK inhibitors blocking WNK kinase signaling
Fujii, Shinya,Ishigami-Yuasa, Mari,Isobe, Kiyoshi,Kagechika, Hiroyuki,Kikuchi, Eriko,Mori, Takayasu,Suzuyama, Honoka,Uchida, Shinichi,Watanabe, Yuko
, (2020/07/21)
We report here structural development of N-(4-phenoxyphenyl)benzamide derivatives as novel SPAK (STE20/SPS1-related proline/alanine-rich kinase) inhibitors. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension, and therefore inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for antihypertensive drugs. Based on the structure of lead compound 2, we examined the SAR of N-(4-phenoxyphenyl)benzamide derivatives, and developed compound 20l as a potent SPAK inhibitor. Compounds 20l is a promising candidate for a new class of antihypertensive drugs.
Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold
Ishikawa, Tomoyasu,Seto, Masaki,Banno, Hiroshi,Kawakita, Youichi,Oorui, Mami,Taniguchi, Takahiko,Ohta, Yoshikazu,Tamura, Toshiya,Nakayama, Akiko,Miki, Hiroshi,Kamiguchi, Hidenori,Tanaka, Toshimasa,Habuka, Noriyuki,Sogabe, Satoshi,Yano, Jason,Aertgeerts, Kathleen,Kamiyama, Keiji
, p. 8030 - 8050 (2012/01/14)
Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
