Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 4, Pages 1930-1950Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00932
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Funding
- NIH [R01CA193609, 1S10OD010678-01, 1S10RR026377-01, R01CA180519, 1R43CA246788-01, 1S10OD016226-01A1, R01CA240447]
- University of Tennessee College of Pharmacy Drug Discovery Center
- Rally
- CURE
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The study reports a structurally optimized dual MDM2/XIAP inhibitor, leading to the discovery of a more potent analogue against EU-1, which exerts dual targeting effects and can induce cell death. The results suggest that the scaffold based on 14 shows promise for further development as a potential therapeutic agent for leukemia and other cancers.
Murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP) are important cell survival proteins in tumor cells. As a dual MDM2/XIAP inhibitor reported previously, compound MX69 has low potency with an IC50 value of 7.5 mu M against an acute lymphoblastic leukemia cell line EU-1. Herein, we report the structural optimization based on the MX69 scaffold, leading to the discovery of a 25-fold more potent analogue 14 (IC50 = 0.3 mu M against EU-1). We demonstrate that 14 maintains its mode of action by dual targeting of MDM2 and XIAP through inducing MDM2 protein degradation and inhibiting XIAP mRNA translation, respectively, which resulted in cancer cell growth inhibition and cell death. The results strongly suggest that the scaffold based on 14 is promising for further optimization to develop a new therapeutic agent for leukemia and possibly other cancers where MDM2 and XIAP are dysregulated.
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