2. Academic Validation
  3. Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors

Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors

  • ACS Med Chem Lett. 2016 Sep 13;7(12):1044-1049. doi: 10.1021/acsmedchemlett.6b00221.
Xiaodong Wang 1,  Jing Liu 1,  Weihe Zhang 1,  Michael A Stashko 1,  James Nichols 2,  Michael J Miley 3,  Jacqueline Norris-Drouin 1,  Zhilong Chen 1,  Mischa Machius 3,  Deborah DeRyckere 4,  Edgar Wood 2,  Douglas K Graham 5,  H Shelton Earp 6,  Dmitri Kireev 1,  Stephen V Frye 6
Affiliations

Affiliations

  • 1 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.
  • 2 Meryx, Inc. , 450 West Dr., Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 27994735 DOI: 10.1021/acsmedchemlett.6b00221
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 EC50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue 3 complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound 16 (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.

Keywords

MerTK; MerTK inhibitors; TAM kinase; macrocycle; pyrrolopyrimidine; structure-based drug design.

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