Development of novel Asf1-H3/H4 inhibitors

Greg F Miknis; Sarah J Stevens; Luke E Smith; David A Ostrov; Mair E A Churchill

doi:10.1016/j.bmcl.2014.11.067

Development of novel Asf1-H3/H4 inhibitors

Bioorg Med Chem Lett. 2015 Feb 15;25(4):963-8. doi: 10.1016/j.bmcl.2014.11.067. Epub 2014 Dec 4.

Authors

Greg F Miknis¹, Sarah J Stevens², Luke E Smith³, David A Ostrov⁴, Mair E A Churchill³

Affiliations

¹ Colorado Center for Drug Discovery, Colorado State University, Department of Chemistry, Fort Collins, CO 80523-1872, USA. Electronic address: Greg.Miknis@Colostate.edu.
² Colorado Center for Drug Discovery, Colorado State University, Department of Chemistry, Fort Collins, CO 80523-1872, USA.
³ Department of Pharmacology and the Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁴ Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610-3633, USA.

Abstract

The histone chaperone anti-silencing function 1 (Asf1) has emerged as a promising target for therapeutic intervention for multiple cancers (Cell2006, 127, 458). Asf1 is involved in the packaging of the eukaryotic genome into chromatin, which is essential for normal growth, development, and differentiation, as this regulates all nuclear processes that use DNA as a substrate. Starting from a collection of HTS leads, we identified a series of N-acyl hydrazones as novel inhibitors of the Asf-histone H3/H4 interaction. These compounds represent the first example of inhibitors capable of disrupting the Asf1-H3/H4 complex.

Keywords: Asf1; Drug discovery; H3/H4; Histone chaperone; Hydrazone.

Publication types

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

MeSH terms

Cell Cycle Proteins / antagonists & inhibitors*
Histones / antagonists & inhibitors*
Humans
Molecular Chaperones

Substances

ASF1A protein, human
Cell Cycle Proteins
Histones
Molecular Chaperones

Abstract

Publication types

MeSH terms

Substances

Grants and funding