Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group.

Abstract

Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro. The potency and selectivity of 19 for MERTK over FLT3 were confirmed in cell-based assays using human cancer cell lines. Compound 19 had favorable pharmacokinetic properties in mice. Phosphorylation of MERTK was decreased by 75% in bone marrow leukemia cells from mice treated with 19 compared to vehicle-treated mice.

• Authors: Jichen Zhao, Dehui Zhang, Weihe Zhang, Michael A Stashko, Deborah DeRyckere, Eleana Vasileiadi, Rebecca E Parker, Debra Hunter, Qingyang Liu, Yuewei Zhang, Jacqueline Norris-Drouin, Bing Li, David H Drewry, Dmitri Kireev, Douglas K Graham, Henry Shelton Earp, Stephen V Frye, Xiaodong Wang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 22 Pg. 10242-10254 (11 21 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30347155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• c-Mer Tyrosine Kinase

Topics

• Animals
• Cell Line, Tumor
• Drug Design
• Humans
• Methylation
• Mice
• Models, Molecular
• Protein Conformation
• Protein Kinase Inhibitors (chemistry, metabolism, pharmacokinetics, pharmacology)
• Pyrimidines (chemistry, metabolism, pharmacokinetics, pharmacology)
• Structure-Activity Relationship
• Tissue Distribution
• c-Mer Tyrosine Kinase (antagonists & inhibitors, chemistry, metabolism)