2. Academic Validation
  3. Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity

Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity

  • J Med Chem. 2020 May 28;63(10):5501-5525. doi: 10.1021/acs.jmedchem.0c00442.
Xiaoyang Li 1 2,  Yuqi Jiang 1,  Yuri K Peterson 2,  Tongqiang Xu 1,  Richard A Himes 3,  Xin Luo 4,  Guilin Yin 4,  Elizabeth S Inks 2,  Nathan Dolloff 5,  Stephanie Halene 6,  Sherine S L Chan 2,  C James Chou 2
Affiliations

Affiliations

  • 1 School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266071, China.
  • 2 Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
  • 3 Department of Chemistry and Biochemistry, College of Charleston, 66 George Street, Charleston, South Carolina 29424, United States.
  • 4 Technology Center of Qingdao Customs, Qingdao, Shandong 266002, China.
  • 5 Department of Cellular and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston SC29425, United States.
  • 6 Section of Hematology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06511, United States.
PMID: 32321249 DOI: 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 antileukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 values against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple Cancer cells with different FLT3 and p53 statuses. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates master antiapoptotic proteins, resulting in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a is incapable of causing Apoptosis at a 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 a higher AUC0-inf value.

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