Discovery of Sphingosine Kinase Inhibition by Modified Quinoline-5,8-Diones

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biochemistry

Background:

• Sphingosine kinase (SphK) is overexpressed in various cancers, promoting tumor growth.
• SphK inhibitors are pursued for cancer therapy, with some showing clinical efficacy.
• Existing inhibitors like PF-543 and opaganib highlight SphK as a drug target.

Purpose of the Study:

• To develop the first quinoline-5,8-dione-based sphingosine kinase inhibitor.
• To explore structure-activity relationships for SphK inhibition using a fragment-based approach.
• To identify novel compounds with potential anticancer properties by targeting SphK.

Main Methods:

• Fragment-based drug design utilizing CB5468139 and PF-543 as structural leads.
• Synthesis and characterization of novel quinoline-5,8-dione derivatives.
• In vitro enzymatic assays against SphK1 and SphK2, and molecular docking studies.

Main Results:

• Eight novel C(7) ether-linked quinoline-5,8-diones were synthesized and screened for SphK1/2 activity.
• Pyrrolidine-based derivatives, particularly compound 21, showed improved SphK1 binding efficacy.
• Molecular modeling indicated favorable docking and binding energies for the pyrrolidine quinoline-5,8-dione scaffold.

Conclusions:

• First-in-class quinoline-5,8-dione-based SphK inhibitors were identified with low micromolar dual SphK1/2 inhibition.
• A potential new binding mode for SphK inhibitors was elucidated.
• While anticancer activity screening was inconclusive, the identified inhibitors represent a promising new chemical framework for further drug development.