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Pyrazolo[3,4‐ d ]pyrimidine derivatives as irreversible Bruton's tyrosine kinase inhibitors
Yeom Hyesu,Achary Raghavendra,Choi Yunha,Park Chi Hoon,Lee Joo‐Youn,Lee Heung Kyoung,Kim Pilho,Cho Sung Yun 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.4
4,6-Disubstituted pyrazolo[3,4-d]pyrimidine derivatives were explored as irreversible Bruton’s tyrosine kinase (BTK) inhibitors. The structure–activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turned out that introducing 1-acrylamido-4-aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3-acrylamido-aniline (1j) as 4-position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell-based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B-cell-mediated hematologic cancers.
Yeonji Kim,이경원,Hyesu Yeom,Miok Kim,Yeon Kyung Lee,이주연,Jong Yeon Hwang,Youngki Min,Do Hyun Ryu,Chang Hoon Lee,조성윤 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.2
5-Aryl-substituted (piperdin-4-yl)pyrimidine-2,4-diamine derivatives were synthesized and their inhibitory activities were evaluated against TAM kinase (Tyro3, Axl, Mer), respectively. Detailed SAR studies on the fifth position of pyrimidine could lead to the discovery of potent and selective TAM kinase inhibitor. Compounds 6f, 7b, and 7f exhibited potent inhibitory activity and excellent selectivity toward Axl, Tyro3 and Mer kinases. Molecular docking studies corroborated that slight changes of substituents induced dramatic structural change of Met596, 623, 674 backbone carbonyl and amide in the hinge region of Axl, Tyro3, Mer, and resulted in different binding poses of 6f, 7b, and 7f, respectively. It was identified as a strong possibility to control selectivity by structural modification of phenyl substituents of pyrimidine as a new class of TAM kinase inhibitors.