UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.

Abstract

We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

• Authors: Weihe Zhang, Deborah DeRyckere, Debra Hunter, Jing Liu, Michael A Stashko, Katherine A Minson, Christopher T Cummings, Minjung Lee, Trevor G Glaros, Dianne L Newton, Susan Sather, Dehui Zhang, Dmitri Kireev, William P Janzen, H Shelton Earp, Douglas K Graham, Stephen V Frye, Xiaodong Wang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 16 Pg. 7031-41 (Aug 28 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25068800 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Piperazines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• UNC2025
• FLT3 protein, human
• MERTK protein, human
• Receptor Protein-Tyrosine Kinases
• c-Mer Tyrosine Kinase
• fms-Like Tyrosine Kinase 3
• Adenine

Topics

• Adenine (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Administration, Oral
• Animals
• Biological Availability
• Cell Line, Tumor (drug effects)
• Chemistry Techniques, Synthetic
• Humans
• Inhibitory Concentration 50
• Leukemia, B-Cell (drug therapy, metabolism, pathology)
• Mice, SCID
• Molecular Targeted Therapy
• Piperazines (administration & dosage, pharmacokinetics, pharmacology)
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays
• c-Mer Tyrosine Kinase
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, metabolism)