ACS Medicinal Chemistry Letters p. 1193 - 1197 (2013)
Update date:2022-07-29
Topics:
Burger, Matthew T.
Han, Wooseok
Lan, Jiong
Nishiguchi, Gisele
Bellamacina, Cornelia
Lindval, Mika
Atallah, Gordana
Ding, Yu
Mathur, Michelle
Mcbride, Chris
Beans, Elizabeth L.
Muller, Kristine
Tamez, Victoriano
Zhang, Yanchen
Huh, Kay
Feucht, Paul
Zavorotinskaya, Tatiana
Dai, Yumin
Holash, Jocelyn
Castillo, Joseph
Langowski, John
Wang, Yingyun
Chen, Min Y.
Garcia, Pablo D.
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM Kis < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.
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