Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity
- 6 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (10), 5501-5525
- https://doi.org/10.1021/acs.jmedchem.0c00442
Abstract
Here we present a new series of hydrazide-bearing class I selective HDAC inhibitors designed based on panobinostat. The cap, linker, and zinc-binding group were derivatized to improve HDAC affinity and anti-leukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple cancer cells with different FLT3 and p53 status. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates the master anti-apoptotic proteins, resulting in the activation of pro-caspase3 in in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a is incapable of causing apoptosis at therapeutic concentration. The MDM2 antagonist and the proteasome inhibitor promote 13a-triggered apoptosis by preventing p53 degradation. Furthermore, we demonstrate that apoptosis rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability and higher AUC0-inf.Keywords
Funding Information
- National Cancer Institute (CA163452)
- National Institute of General Medical Sciences (P20GM103542)
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