Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology

• Type of Material: Article
• Authors: Chenxiao Da, University of North Carolina; Dehui Zhang, University of North Carolina; Michael Stashko, University of North Carolina; Eleana Vasileiadi, Emory University; Rebecca Parker, Emory University; Katherine Minson, Emory University; Madeline G. Huey, Emory University; Justus M. Huelse, Emory University; Debra Hunter, University of North Carolina; Thomas S. K. Gilbert, University of North Carolina; Jacqueline Norris-Drouin, University of North Carolina; Michael Miley, University of North Carolina; Laura E. Herring, University of North Carolina; Lee M. Graves, University of North Carolina; Deborah DeRyckere, Emory University; H. Shelton Earp, University of North Carolina; Douglas Graham, Emory University; Stephen V. Frye, University of North Carolina; Xiaodong Wang, University of North Carolina; Dmitri Kireev, University of North Carolina
• Language: English
• Date: 2019-10-02
• Publisher: AMER CHEMICAL SOC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Chemical Society
• Final Published Version (URL): http://dx.doi.org/10.1021/jacs.9b08660
• Title of Journal or Parent Work: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• Volume: 141
• Issue: 39
• Start Page: 15700
• End Page: 15709
• Grant/Funding Information: This work was supported by the University Cancer Research Fund (UCRF), Federal Funds from the National Cancer Institute, National Institute of Health, under Contract No. HHSN261200800001E, and a philanthropic gift to the CICBDD. We thank Dr. Brenda Temple for her help in depositing the X-ray crystallographic structure to the Protein Data Bank (PDB). This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center.
• Keywords: Physical Sciences; RECEPTOR TYROSINE KINASES; Science & Technology; Chemistry; Chemistry, Multidisciplinary; INHIBITION; QSAR; TARGETS; PROTEIN-LIGAND COMPLEXES; PREDICTION; DRUG DISCOVERY; FAMILY

Abstract

Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.