We and others have hypothesized that inhibiting SphK1 is a powerful therapeutic strategy in pathologies that are characterized by cell hyperproliferation, e.g. cancer and fibrosis. This hypothesis was generated largely through the use interfering RNA strategies - there is a paucity of potent, selective small molecule inhibitors of SphKs. Sphingosine kinase type 1 (SphK1) has been implicated in a variety of disease processes in animal models of human diseases such as cancer and fibrosis. SphynKx Therapeutics (SKX) has licensed proprietary, amidine-based SphK1 inhibitors that are both potent (~100 nM) and selective (~500 fold), but these are suboptimal in that they are metabolized rapidly in vivo. Herein we outline a set of strategies including pro-drug forms, modified amidines, guanidines, etc. to render the SphK1 inhibitors drug like. These new chemical entities will be tested first in broken and whole cell assays of SphK1 activity and, if suitable, taken into rats for pharmacokinetic analysis. The optimized, drug-like SKX inhibitors to make them drug-like will enable phase II of the project, i.e. testing an SphK1 inhibitor in animal models of disease. Such drugs are required to validate SphK1 as a drug target and to identify the SKX compound to take forward as an Investigational New Drug.
Sphingosine kinase type 1 (SphK1) has been implicated in a variety of disease processes in animal models of human disease such as cancer and fibrosis. Until recently, high potency small molecule inhibitors of SphK1 were not available. SphynKx Therapeutics (SKX) has proprietary SphK1 inhibitors that are both selective and potent. However, the current SKX inhibitors are suboptimal in that they are metabolized rapidly in vivo. The current proposal outlines a plan to optimize the lead SKX inhibitors to make them drug-like and thus enable the next phase of this work - testing the inhibitors in animal models of disease. Such inhibitors are required to validate SphK1 inhibition as a drug target and to identify the SKX compound to take forward as an Investigational New Drug.
