title: Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors.
abstract: Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC50below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue3complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound16(UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.affiliation: Meryx, Inc. , 450 West Dr., Chapel Hill, North Carolina 27599, United States.
authors.forename: James
authors.initials: J
authors.lastname: Nichols
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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: Jacqueline
authors.initials: J
authors.lastname: Norris-Drouin
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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: Zhilong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Mischa
authors.initials: M
authors.lastname: Machius
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, School of Medicine, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.affiliation: Meryx, Inc. , 450 West Dr., Chapel Hill, North Carolina 27599, United States.
authors.forename: Edgar
authors.initials: E
authors.lastname: Wood
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia 30322, United States; Meryx, Inc., 450 West Dr., Chapel Hill, North Carolina 27599, United States.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States; Meryx, Inc., 450 West Dr., Chapel Hill, North Carolina 27599, United States.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, 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; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States; Meryx, Inc., 450 West Dr., Chapel Hill, North Carolina 27599, United States.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
keywords: MerTK; MerTK inhibitors; TAM kinase; macrocycle; pyrrolopyrimidine; structure-based drug design