Description:
Novel class I HDAC inhibitors that are impervious to glucuronidation for the treatment of hematologic malignancies and inflammatory diseases/disorders
Technology:
MUSC researchers have developed a series of potent and selective class I histone deacetylase (HDAC) inhibitors that do not suffer from the genotoxicity, off-target effects, and metabolic inactivation of the current first generation HDAC inhibitors. Additionally, the lead MUSC compound LP-411 demonstrates vastly superior pharmacological properties in max serum concentration, total biological exposure and bioavailability as compared to the recently approved multiple myeloma therapy Panobinostat, and even the current best lead in PK class under clinical development Pracinostat.
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. In vivo data in an AML mouse models demonstrates that LP-411 has a significant effect in prolonging survival and maintaining weight. In addition, HDAC inhibitor clinical efficacy is linked to the malignancy’s p53 status. Our current next generation HDAC inhibitors (unpublished) have overcome this challenge and induce selective toxicity in p53 mutant AML cells (cell lines and primary cells from patients).
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, lymphoma 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: US Application 16/340,458 filed April 9, 2019
MUSC-FRD Technology ID: P1704