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

Danny C Lenstra1, Eddy Damen2, Ruben G G Leenders2

  • 1Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.

Chemmedchem
|June 6, 2018
PubMed

Insights

Researchers explored structure-activity relationships of SETD7 inhibitors, focusing on (R)-PFI-2 analogues. This work advances the development of novel epigenetic drugs targeting SETD7 for diseases like cancer.

Area of Science:

  • Epigenetics
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • SETD7 is a histone methyltransferase crucial for human gene regulation.
  • Dysregulated SETD7 expression is linked to various diseases, notably cancer.
  • SETD7 represents a promising target for novel epigenetic drug development.

Purpose of the Study:

  • To conduct structure-activity relationship (SAR) studies on the potent SETD7 inhibitor (R)-PFI-2 and its analogues.
  • To synthesize and evaluate a library of 29 analogues for their inhibitory effects on human SETD7.
  • To elucidate key molecular interactions between inhibitors and SETD7.

Main Methods:

  • Synthesis of 29 structural analogues of (R)-PFI-2.
  • In vitro evaluation of analogue inhibition against recombinantly expressed human SETD7.
  • Analysis of key binding interactions between inhibitors and SETD7 residues.

Main Results:

  • A library of 29 (R)-PFI-2 analogues was synthesized and tested.
  • Key interactions driving SETD7 inhibition were identified.
  • A salt bridge between the inhibitor's NH2+ group and Asp256, and a hydrogen bond with His252 were critical.

Conclusions:

  • Structure-activity relationship studies provide insights into potent SETD7 inhibition.
  • Understanding these interactions can guide the design of more effective SETD7-targeting epigenetic drugs.
  • This research contributes to the development of new therapeutic strategies for SETD7-associated diseases.
Keywords:
(R)-PFI-2SETD7epigeneticshistone lysine methyltransferasestructure-activity relationships

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