Novel Acid Ceramidase Inhibitors for Oncology and Hyperproliferative Skin Disorders

Summary

Acid ceramidase (AC) catalyzes the hydrolysis of the lipid messenger ceramide thereby regulating ceramide levels in cells. AC is involved in multiple physiological and pathological processes, including cancer resistance and neuropathic pain. Previous AC inhibitors are ceramide analogs with weak inhibitory activity in vitro and virtually no utility in vivo. 

The present portfolio of inventions provides two chemically distinct classes of small-molecule inhibitors of intracellular AC activity, which act at single digit nanomolar concentrations in vitro and at low doses in vivo.

Highlights of the Project

• Single digit nanomolar potency in vitro against AC activity.
• SAR studies reveal critical structural features associated with AC inhibition.
• All compounds are new chemical entities.
• Promising hits have been advanced to in vivo models of cancers (melanoma, colon) and proliferative diseases of the skin.
• Worldwide composition of matter patent claims pending.
• Useful in treating diseases or disorders involving cell over proliferation and/or dysfunctional sphingolipid signal transduction.
• Compounds useful to sensitize tumor cells to current anticancer drugs and radiation therapy (can increase potency of standard chemotherapies 10-20X).

We are currently looking for commercial partners to further develop these AC inhibitors for treatment of cancers and other disorders in which modulation of the levels of ceramide is clinically relevant.

Patent Status

Publications

Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR). J. Med. Chem., 2013, 56(9):3518-3530 PubmedID: 23614460

      Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Sci Rep. 2013; 3: 1035.  PubmedID: 23301156

Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase. Angew Chem 2014 Nov 13. doi: 10.1002/anie.201409042.