Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology

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 TYR...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2019-10, Vol.141 (39), p.15700-15709
Main Authors: Da, Chenxiao, Zhang, Dehui, Stashko, Michael, Vasileiadi, Eleana, Parker, Rebecca E, Minson, Katherine A, Huey, Madeline G, Huelse, Justus M, Hunter, Debra, Gilbert, Thomas S. K, Norris-Drouin, Jacqueline, Miley, Michael, Herring, Laura E, Graves, Lee M, DeRyckere, Deborah, Earp, H. Shelton, Graham, Douglas K, Frye, Stephen V, Wang, Xiaodong, Kireev, Dmitri
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
antineoplastic agents
Antineoplastic Agents - chemistry
Cell Line, Tumor
cell lines
Cell Survival - drug effects
Gene Expression Regulation, Neoplastic - drug effects
Humans
lung neoplasms
Mice
Molecular Structure
myeloid leukemia
neoplasm cells
Neoplasms, Experimental
pharmacodynamics
phenotype
phosphotransferases (kinases)
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
therapeutics
tyrosine
X-ray diffraction
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Summary: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.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.9b08660