NU 2025-154

INVENTORS

• Karl Scheidt*

• Gina Connors

SHORT DESCRIPTION

This technology introduces novel covalent inhibitors of MEK4, built upon previously-developed reversible inhibitors (see NU2019-059 and NU2021-217). A covalent inhibition strategy offers enhanced potency, selectivity, and prolonged duration of action compared to reversible inhibitors, allowing for the development of more effective therapies targeting MEK4.

BACKGROUND

MEK4 is an upstream kinase in the MAPK signaling pathway that phosphorylates p38 MAPK and c-Jun N-terminal kinase (JNK) in response to mitogenic and cellular stress queues. These pathways are involved in cell growth and differentiation, apoptosis, inflammation, and response to cellular stress. Dysregulation of MEK4 and the related MAP kinase kinase, MEK7, are implicated in several types of cancer. However, selective pharmacological attenuation of MEK4 remains challenging. Optimization of a covalent inhibitor in this space remains crucial towards developing chemical toolsets and as starting points for drug discovery programs targeting MEK4.

ABSTRACT

This invention discloses a series of indazole-based compounds, including 6-fluoro-3-phenyl-IH-indazole variants, designed to modulate MEK4 activity. Acrylamide handles with differing steric and electronic properties were implemented for covalent engagement to enhance potency over reversible inhibitors and increase selectivity for MEK4 over MEK7. The researchers generated MEK4-ligand covalent adduct crystals to enhance structure-based inhibitor design. Preliminary in vitro studies validate the compounds’ selective inhibition and cellular efficacy for attenuating JNK phosphorylation.

DEVELOPMENT STAGE

TRL-3 - Experimental Proof-of-Concept: Key inhibitory functions have been validated in in-vitro biochemical assays, supporting the feasibility of the technology.

APPLICATIONS

• Targeted treatment for cell proliferative diseases associated with aberrant MEK4 activity.

• Drug development tool compound for targeting MEK4 and MEK7.

ADVANTAGES

• Covalent inhibition strategy to enhance the potency of MEK4 inhibition compared to reversible inhibitors.

• Preliminary single-digit nM potency in biochemical reporter assays, which is being further optimized and validated.

• Selective targeting of MEK4 over MEK7.

IP STATUS

A provisional patent application has been filed.