Structure-Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

Danny C Lenstra; Eddy Damen; Ruben G G Leenders; Richard H Blaauw; Floris P J T Rutjes; Anita Wegert; Jasmin Mecinović

doi:10.1002/cmdc.201800242

Structure-Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

ChemMedChem. 2018 Jul 18;13(14):1405-1413. doi: 10.1002/cmdc.201800242. Epub 2018 Jun 25.

Authors

Danny C Lenstra¹, Eddy Damen², Ruben G G Leenders², Richard H Blaauw³, Floris P J T Rutjes¹, Anita Wegert², Jasmin Mecinović¹

Affiliations

¹ Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
² Mercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, The Netherlands.
³ Chiralix, Toernooiveld 100, 6525 EC, Nijmegen, The Netherlands.

PMID: 29869845
DOI: 10.1002/cmdc.201800242

Abstract

SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small-molecule inhibitors have been reported that target SETD7, the most potent being (R)-PFI-2. Herein we report structure-activity relationship studies on (R)-PFI-2 and its analogues. A library of 29 structural analogues of (R)-PFI-2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)-PFI-2's NH₂⁺ group and SETD7's Asp256 and His252 residue, respectively.

Keywords: (R)-PFI-2; SETD7; epigenetics; histone lysine methyltransferase; structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Epigenesis, Genetic / drug effects
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / chemistry
Histone-Lysine N-Methyltransferase / metabolism
Humans
Molecular Docking Simulation
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry*
Pyrrolidines / pharmacology*
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacology*
Tetrahydroisoquinolines / chemical synthesis
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / pharmacology*

Substances

(R)-PFI-2
Enzyme Inhibitors
Pyrrolidines
Recombinant Proteins
Small Molecule Libraries
Sulfonamides
Tetrahydroisoquinolines
Histone-Lysine N-Methyltransferase
SETD7 protein, human