Improved MEK4 Inhibitors for the Treatment of Cancer

NU 2021-217

INVENTORS

• Karl Scheidt*
• Ada Jade Kwong
• Hidayatullah Munshi
• Thao Nguyen Pham

SHORT DESCRIPTION

This technology introduces novel indazole derivatives as potent and selective MEK4 inhibitors for cancer treatment, particularly in advanced prostate cancer and pancreatic adenocarcinoma. The lead molecule is optimized over first-generation compounds with enhanced potency and cell permeability properties. 

BACKGROUND

MEK4 is a MAPK/ERK kinase within the MAPK signaling pathway that directly activate MAP kinases kinases responsible for orchestrating cellular growth and stress responses. There are limited MEK4 inhibitors available, and the existing compounds have low potency and selectivity profiles, several of which have significant off-target effects.  There is great need for a selective and pharmacologically robust MEK4 inhibitor, both as a tool compound for studying MEK4 molecular mechanisms and as a staring point for drug discovery programs targeting MEK4.

ABSTRACT

The invention comprises optimized indazole compounds and derivatives designed as selective inhibitors of MEK4. These compounds – including both 3-arylindazoles and 3-amino-indazoles – modulate MEK4 activity to significantly decrease phosphorylation of downstream targets such as JNK and lead to antiproliferative effects against pancreatic cell lines. When combined with MEK1/2 inhibitors, MEK4 inhibition demonstrates even greater synergistic anti-proliferative effects against pancreatic cancer cells. The inhibitors therefore provide a chemical probe for studying MAPK pathway crosstalk in oncogenesis and offer a novel therapeutic strategy for treating cell proliferative diseases.

APPLICATIONS

• Development of MEK4 inhibitors as treatments for pancreatic adenocarcinoma and advanced prostate cancer.
• Combination therapy with MEK1/2 inhibitors may achieve synergistic anti-proliferative effects.
• Oncology research tool to perform MEK4 target validation and study MAPK signaling crosstalk in cancer.

ADVANTAGES

• High potency – IC50 values of <100 nM in reporter assays.
• High selectivity – improved specificity for MEK4 over other MEK kinases.
• Cell permeability – efficacy in cell-based assays for JNK phosphorylation and proliferation.
• Synergistic potential – May enhance the efficacy of combination therapies with MEK1/2 inhibitors.

PUBLICATIONS

• Karl Scheidt et al, Rational Design, Optimization, and Biological Evaluation of Novel MEK4 Inhibitors against Pancreatic Adenocarcinoma, ACS Med. Chem. Lett, 2021

IP STATUS

US Patent Pending 18/466,599