3-Arylindazoles as Selective MEK4 Inhibitors

NU 2019-059

INVENTORS

• Karl Scheidt*
• Matthew Clutter
• Ada Jade Kwong
• Gary Schiltz

SHORT DESCRIPTION

This technology discloses novel 3-arylindazole compounds as highly potent and selective MEK4 inhibitors for treating various cancers, including metastatic prostate cancer. The compounds offer promise both as clinical agents and valuable chemical probes for oncology research.

BACKGROUND

MEK4 is an upstream kinase within the MAPK signaling cascade, implicated in cancer progression and metastasis, particularly in advanced prostate cancer. The value of MEK4 as an oncology target had not previously been pharmacologically validated due to low potency and selectivity of chemical probes for MEK4, underscoring the need for a robust, highly selective inhibitor that can lend confidence in MEK4 target validation and therapeutic development.

ABSTRACT

The invention comprises novel indazole compounds—specifically, 3-arylindazoles—designed as selective inhibitors of MEK4. Through molecular modeling, structure-activity relationship studies, and cellular testing, the inventors optimized the novel series of compounds as the first of their kind in both activity and selectivity. Also included in the invention are pharmaceutical compositions and methods of treatment of cancers associated with MEK4 overactivity.

APPLICATIONS

• Tool compound for MEK4 target validation research.
• Drug development for cancers associated with aberrant MEK4 activity.

ADVANTAGES

• High selectivity – >150-fold selectivity for MEK4 over any other MEK kinase.
• Potent activity – IC50 values of <100 nM for p38 and JNK phosphorylation.
• Novel tool for MEK4 target validation and cancer research.

PUBLICATIONS

• Scheidt et al, Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors, ChemMedChem, 2019

IP STATUS

Issued US Patent 11,370,770