Journal of Medicinal Chemistry p. 8373 - 8386 (2015)
Update date:2022-07-30
Topics:
Burger, Matthew T.
Nishiguchi, Gisele
Han, Wooseok
Lan, Jiong
Simmons, Robert
Atallah, Gordana
Ding, Yu
Tamez, Victoriano
Zhang, Yanchen
Mathur, Michelle
Muller, Kristine
Bellamacina, Cornelia
Lindvall, Mika K.
Zang, Richard
Huh, Kay
Feucht, Paul
Zavorotinskaya, Tatiana
Dai, Yumin
Basham, Steve
Chan, Julie
Ginn, Elaine
Aycinena, Alex
Holash, Jocelyn
Castillo, Joseph
Langowski, John L.
Wang, Yingyun
Chen, Min Y.
Lambert, Amy
Fritsch, Christine
Kauffmann, Audry
Pfister, Estelle
Vanasse, K. Gary
Garcia, Pablo D.
Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.
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