Chemogenomic Landscape of RUNX1-mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity.

Purpose:RUNX1-mutated (RUNX1mut) acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Toward this goal, we further dissected the mutational spectrum and gene expression profile of RUNX1mut AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup.Experimental Design: RNA-sequencing of 47 RUNX1mut primary AML specimens was performed and sequencing results were compared to those of RUNX1 wild-type samples. Chemical screens were also conducted using RUNX1mut specimens to identify compounds selectively affecting the viability of RUNX1mut AML.Results: We show that samples with no remaining RUNX1 wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most RUNX1mut specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the glucocorticoid receptor (GR). We observed that specimens harboring RUNX1 mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that coassociating mutations as well as GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating RUNX1 expression in human AML cells.Conclusions: Our findings show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. Clin Cancer Res; 23(22); 6969-81. ©2017 AACR.

2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as potent dissociated glucocorticoid receptor agonists.

A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX). It displayed a dissociated profile by exhibiting 42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV) luciferase reporter transactivation assay. Compound 13 and analogues containing heterocyclic replacements for the C2 phenyl and modified B rings showed high repression of TNFα production in human whole blood, with IC50 values (43-167 nM) approaching the level of DEX (21 nM). On the basis of X-ray structures and force field calculations, the overall potency of this series was attributed to a favorable conformation of the C2α phenyl, induced by the neighboring C3α methyl.

Octahydrophenanthrene-2,7-diol analogues as dissociated glucocorticoid receptor agonists: discovery and lead exploration.

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.

Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors.

In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.

Palladium-catalyzed cross-coupling reactions of benzyl indium reagents with aryl iodides.

Herein described is an operationally simple procedure for generating benzyl indium species from readily available benzyl bromides and indium metal followed by in situ palladium-catalyzed coupling with aryl halides. The procedure provides diarylmethanes in modest to excellent yield and tolerates a variety of functional groups in both coupling partners.

Sulfamides as novel histone deacetylase inhibitors.

The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.