Abstract
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.
Keywords:
BTK; DLBCL; IRAK4; Mutant MyD88; Pyrrolotriazine.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Caco-2 Cells
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Dogs
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Drug Design
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Half-Life
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Hepatocytes / cytology
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Hepatocytes / metabolism
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Humans
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Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / pathology
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Molecular Dynamics Simulation
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Mutation
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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Permeability / drug effects
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Protein Kinases / chemistry
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Protein Kinases / metabolism
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Pyrroles / chemistry*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Rats
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Structure-Activity Relationship
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Thiazines / chemistry*
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Thiazines / pharmacokinetics
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Thiazines / pharmacology
Substances
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1H-pyrrolo(1,2-c)(1,3)thiazine
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Myeloid Differentiation Factor 88
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Pyrroles
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Thiazines
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Protein Kinases
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases