Long chain base sphingosine kinase inhibitors
Patent Number: US9688668B2
Executive Summary:
General Description:
Traditional methods of inhibiting kinases, including sphingosine kinases, have centered on targeting the ATP binding site of the kinase, a strategy that has enjoyed moderate success. However, such methods suffer from lack of selectivity across a wide array of kinases. Additionally, the amino acid sequence of the ATP binding domain of SphKl and SphK2 is conserved across a number of diacylglycerol (DAG) kinase family members, rendering the traditional strategy problematic because it does not discriminate among kinases. By contrast, the inhibitors in the present invention are competitive with sphingosine, not with ATP, and thus are not expected to inhibit other protein and diacylglycerol kinases.
Currently, there is a need for novel, potent, and selective agents that inhibit the sphingosine substrate-binding domain of the sphingosine kinases (e.g., human SphKl or SphK2, or both) that have enhanced potency, selectivity, and bioavailability. In addition, there is a need in the art for identification, as well as the synthesis and use, of such compounds. The present invention satisfies these needs.
Scientific Progress:
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Publications:
Endothelial Dysfunction in AKI
Inventor Bio: Kevin R. Lynch
https://med.virginia.edu/faculty/faculty-listing/krl2z
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Active
- Patent Link: https://patents.google.com/patent/US9688668B2/
- Research Institute: University of Virginia, Virginia Tech
- Disease Focus: Inflammatory kidney disease
- Basis of Invention: Novel compounds with selective inhibition of SphK2 enzymatic activity
- How it works: The inhibition of the enzymatic activity of sphingosine kinase – SphK – (which can reduce levels of S1P) can prevent the hyperproliferation of immune cells that are important for inflammation
- Lead Challenge Inventor: Kevin R. Lynch
- Inventors: Webster L. Santos, Kevin R. Lynch, Timothy L. MacDonald, Andrew Kennedy, Yugesh Kharel, Mithun Rajendra Raje, Joseph Houck
- Development Stage: Lead optimization (12 months to IND candidate)
- Novelty:
- Generic and specific intermediates as well as the synthetic compound processes
- Clinical Applications:
- Hyperproliferative disorder
- Cancer
- Hypertensive disease or disorder
- Inflammatory disease or disorder
- Fibrosis
General Description:
Traditional methods of inhibiting kinases, including sphingosine kinases, have centered on targeting the ATP binding site of the kinase, a strategy that has enjoyed moderate success. However, such methods suffer from lack of selectivity across a wide array of kinases. Additionally, the amino acid sequence of the ATP binding domain of SphKl and SphK2 is conserved across a number of diacylglycerol (DAG) kinase family members, rendering the traditional strategy problematic because it does not discriminate among kinases. By contrast, the inhibitors in the present invention are competitive with sphingosine, not with ATP, and thus are not expected to inhibit other protein and diacylglycerol kinases.
Currently, there is a need for novel, potent, and selective agents that inhibit the sphingosine substrate-binding domain of the sphingosine kinases (e.g., human SphKl or SphK2, or both) that have enhanced potency, selectivity, and bioavailability. In addition, there is a need in the art for identification, as well as the synthesis and use, of such compounds. The present invention satisfies these needs.
Scientific Progress:
- Protective effects are also present in the UUO model of renal injury/fibrosis
Future Directions:
- Preclinical studies for IND Approval
Strengths:
- Very few programs in clinical development targeting SphKI or SphK2
Weaknesses:
- Previous S1P agonist already in clinical trials
Patent Status:
- Priority date: 2012-02-08
- Filing date: 2015-07-30
- Publication date: 2017-06-27
- Grant date: 2017-06-27
Publications:
Endothelial Dysfunction in AKI
- Molitoris BA. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest. 2014 Jun;124(6):2355-63.
- Verma SK et al. Renal Endothelial Injury and Microvascular Dysfunction in Acute Kidney Injury. Semin Nephrol. 2015 Jan;35(1):96-107.
- Olivera A et al. Shaping the landscape: metabolic regulation of S1P gradients. Biochim Biophys Acta. 2013 Jan;1831(1):193-202.
- Sensken SC et al. Redistribution of sphingosine 1-phosphate by sphingosine kinase 2 contributes to lymphopenia. J Immunol. 2010 Apr 15;184(8):4133-42.
- Camerer E et al. Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest. 2009 Jul;119(7):1871-9.
- Marsolais D et al. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov. 2009 Apr;8(4):297-307.
- Itagaki K et al. Sphingosine 1-phosphate has dual functions in the regulation of endothelial cell permeability and Ca2+ metabolism. J Pharmacol Exp Ther. 2007 Oct;323(1):186-91.
- Liu Y et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest. 2000 Oct;106(8):951-61.
- Bartels K et al. Sphingosine-1-phosphate receptor signaling during acute kidney injury: the tissue is the issue. Kidney Int. 2014 Apr;85(4):733-5.
- Ham A et al. Selective deletion of the endothelial sphingosine-1-phosphate 1 receptor exacerbates kidney ischemia–reperfusion injury. Kidney Int. 2014; 85: 807–823.
- SW Park et al. Sphingosine kinase 1 protects against renal ischemia-reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation. Kidney Int. 2011 Dec;80(12):1315-27.
- Kharel et al. Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. Biochem J. 2011 Dec 15;440(3):345-53.
- Kharel et al. Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate. Biochem J. 2012 Oct 1;447(1):149-57.
- Kharel et al. Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels. J Pharmacol Exp Ther. 2015 Oct;355(1):23-31.
- Chawla LS et al. Acute Kidney Injury and Chronic Kidney Disease as Interconnected Syndromes. N Engl J Med 2014;371:58-66.
Inventor Bio: Kevin R. Lynch
https://med.virginia.edu/faculty/faculty-listing/krl2z