title: Pseudo-cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new Mer kinase inhibitors.
abstract: Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogues as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer.
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery and ‡Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.forename: Dehui
authors.initials: D
authors.lastname: Zhang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.forename: Debra
authors.initials: D
authors.lastname: Hunter
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.forename: Christopher
authors.initials: C
authors.lastname: Cummings
authors.forename: Minjung
authors.initials: M
authors.lastname: Lee
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Norris-Drouin
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Stewart
authors.forename: Susan
authors.initials: S
authors.lastname: Sather
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Gregory
authors.initials: G
authors.lastname: Kirkpatrick
authors.forename: Mischa
authors.initials: M
authors.lastname: Machius
authors.forename: William P
authors.initials: WP
authors.lastname: Janzen
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003500:Cyclization; D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D003511:Cyclohexanols; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; C586741:UNC2250; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase