NU 2023-060
INVENTORS
Karl Scheidt*
Dalton Kim
Meghan Orr
SHORT DESCRIPTION
Rational design of highly potent and selective covalent MEK7 inhibitors
BACKGROUND
Acute lymphoblastic leukemia (ALL) is a deadly blood cancer, the most common hematological malignancy in patients under 14 years of age. Despite advancements in treatment, ALL relapse continues to be the leading cause of cancer-related mortality in children. Epigenetic silencing and decreased expression of Kruppel-like factor 4 (KLF4) have been linked to pediatric and treatment-resistant cases of ALL. Normally, KLF4 represses transcription of mitogen activated protein kinase 7 (MAP2K7 or MEK7), which regulates a variety of cellular functions including proliferation and differentiation. Loss of MEK7 repression in ALL and consequent amplification of downstream mitogen-activated protein kinase (MAPK) signaling via the only known MEK7 substrate, c-Jun N-terminal kinase (JNK), is thought to contribute to T-cell ALL (T-ALL) pathology. Inhibition of MEK7 or JNK has been shown to reduce leukemic expansion in patient-derived xenograft mouse models. Because JNK has additional roles in genome stability that are MEK7-independent, inhibition of MEK7 represents a more direct approach to target MAPK signaling amplification in T-ALL. MEK7 inhibitors developed by others have significant potency and selectivity issues.
ABSTRACT
Northwestern researchers synthesized a series of benzylamine-functionalized pyrimidines through a streamlined one-pot synthesis, and further optimized structural features to enhance potency of MEK7 inhibition and selectivity for MEK7 over other kinases. The lead compound, DK2403, exhibited potent covalent engagement and biochemical inhibition of MEK7 (10 nM) with minimal activity against off-target kinases (selectivity score = 0.011), including MEK4 and JNK isoforms. Additionally, this compound demonstrated marked cellular cytotoxicity in multiple T-ALL cell lines and significantly attenuated JNK phosphorylation. These results suggest its potential as a targeted therapy for pediatric T-ALL.
APPLICATIONS
ADVANTAGES
Increased selectivity, reducing off-target effects on other kinases
High potency against MEK7
Covalent binding mechanism for prolonged therapeutic effects
PUBLICATION
Scheidt, K, et. al. (2023) The Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors. ACS Medicinal Chemistry Letters, 14(5): 606-13. doi: 10.1021/acsmedchemlett.3c00029.
IP STATUS
US patent application filed.
Cellular cytotoxicity of four T-ALL lines treated with lead MEK7 inhibitor, DK2403.