A 2,6,9-hetero-trisubstituted purine inhibitor exhibits potent biological effects against multiple myeloma cells |
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| Authors: | Vijay M Shahani Daniel P Ball Allan V Ramos Zhihua Li Paul A Spagnuolo Sina Haftchenary Aaron D Schimmer Suzanne Trudel Patrick T Gunning |
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| Institution: | 1. Department of Chemistry, University of Toronto, 3359 Mississauga Road North, Mississauga, ON, L5L 1C6, Canada;2. Princess Margaret Hospital, McLaughlin Centre for Molecular Medicine, 620 University Avenue, Toronto, ON, M5G 2C1, Canada;3. Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Toronto, ON, M5G 2M9, Canada |
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| Abstract: | A focused library of hetero-trisubstituted purines was developed for improving the cell penetrating and biological efficacy of a series of anti-Stat3 protein inhibitors. From this SAR study, lead agent 22e was identified as being a promising inhibitor of MM tumour cells (IC50’s <5 μM). Surprisingly, biophysical and biochemical characterization proved that 22e was not a Stat3 inhibitor. Initial screening against the kinome, prompted by the purine scaffold’s history for targeting ATP binding pockets, suggests possible targeting of the JAK family kinases, as well for ABL1 (nonphosphorylated F317L) and AAK1. |
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| Keywords: | Purine scaffold Multiple myeloma Stat3 Kinome Cancer therapeutics |
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