Novel class I HDAC inhibitors that are impervious to glucuronidation for the treatment of hematologic malignancies and inflammatory diseases/disorders

Description:

MUSC researchers have developed a series of potent and selective class I histone deacetylase (HDAC) inhibitors. Currently, approved HDAC inhibitors are generated using hydroxamic acid or a benzylic amine motif and suffer from toxicity, off-target effects, and metabolic inactivation.  Furthermore, the first generation HDAC inhibitors have been shown to be genotoxic both in vitro and in vivo.  The genotoxicity has mainly been attributed to their hydroxamic acid metal chelation moiety, a known inducer of DNA damage.  Thus, this genotoxicity strictly limits first generation HDAC inhibitors to cancer chemotherapeutics. 

 

The current series of compounds were generated using a novel multi-valent hydrazide motif, which has resulted in selective class I HDAC inhibitors that are impervious to glucuronidation, are Ames negative (non-genotoxic), and possess picomolar to nanomolar potency.  Preliminary in vitro and ex vivo characterization of the lead analogues’ efficacy, selectivity, and toxicity profiles demonstrate that they possess low nanomolar activity against models of acute myeloid leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells and human peripheral blood mononuclear cells (Figure 1). Further, these compounds also display mixed/noncompetitive inhibition, which indicates that they are binding to an allosteric site. Allosteric binding provides numerous advantages in drug development, which could result in lower toxicity and higher specificity to target.

 

In addition, these inhibitors are effective at one twentieth of the concentration of vorinostat at preventing macrophage nitric oxide production and HMGB-1 (a late stage sepsis and an inflammatory bowel disease biomarker) cytokine secretion (Figure 2).  Unlike the first generation hydroxamic acid-based HDAC inhibitors, hydrazides are stable in the presence of liver microsomes.  Since hydrazide does not chelate metal tightly, the propensity for genotoxicity is lowered, thereby eliminating a major barrier to use HDAC inhibitors as viable treatments for diseases other than cancer. 

 

Overview:

Multiple HDAC inhibitors have been approved by the FDA for the treatment of T-cell lymphoma and multiple myeloma (MM). In addition, selective HDAC inhibitors have shown great promise with preclinical models of inflammatory diseases/disorder and cognitive dysfunction and traumatic brain injury.

 

Although effective, approved HDAC inhibitors are commonly associated with dose-limiting toxicities, and are genotoxic.  In addition, large doses of current HDAC inhibitors must be used, which may in part be due to metabolic glucuronidation of the active motif.

 

 

Applications: Therapies for leukemia and lymphoma cancer and inflammatory diseases

Advantages: Selective HDAC I inhibitor, impervious to glucuronidation, picomolar-nanomolar potency, promising toxicity profile, potential allosteric modulator

Key Words: Cancer, leukemia, lymphoma, acute myeloid leukemia, HDAC, HDAC inhibitor

 

Publication: McClure, Jesse J., et al. "Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia." Journal of Medicinal Chemistry 59.21 (2016): 9942-9959.

 

Inventors: James Chou, Elizabeth Inks, Jesse McClure & Cheng Zhang

Patent Status: Provisional filed 10/13/2016

MUSC-FRD Technology ID: P1704

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
hankinsm@musc.edu
Inventors:
Chung-Jen (James) Chou
Jesse McClure
Cheng Zhang
Elizabeth Inks
Keywords:
© 2017. All Rights Reserved. Powered by Inteum