4 research outputs found
Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2<i>H</i>)‑ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors
A new
enhancer of zeste homolog
2 (EZH2) inhibitor series comprising a substituted phenyl ring
joined to a dimethylpyridone moiety via an amide linkage has been
designed. A preferential amide torsion that improved the binding properties
of the compounds was identified for this series via computational
analysis. Cyclization of the amide linker resulted in a six-membered
lactam analogue, compound <b>18</b>. This transformation significantly
improved the ligand efficiency/potency of the cyclized compound relative
to its acyclic analogue. Additional optimization of the lactam-containing
EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement,
which provided compound <b>31.</b> Compound <b>31</b> displayed
improved LipE and on-target potency in both biochemical and cellular
readouts relative to compound <b>18</b>. Inhibitor <b>31</b> also displayed robust in vivo antitumor growth activity and dose-dependent
de-repression of EZH2 target genes
Correction to Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2<i>H</i>)‑ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors
Correction to Design
and Synthesis of Pyridone-Containing
3,4-Dihydroisoquinoline-1(2<i>H</i>)‑ones as a Novel
Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitor
Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2<i>H</i>)‑ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors
A new
enhancer of zeste homolog
2 (EZH2) inhibitor series comprising a substituted phenyl ring
joined to a dimethylpyridone moiety via an amide linkage has been
designed. A preferential amide torsion that improved the binding properties
of the compounds was identified for this series via computational
analysis. Cyclization of the amide linker resulted in a six-membered
lactam analogue, compound <b>18</b>. This transformation significantly
improved the ligand efficiency/potency of the cyclized compound relative
to its acyclic analogue. Additional optimization of the lactam-containing
EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement,
which provided compound <b>31.</b> Compound <b>31</b> displayed
improved LipE and on-target potency in both biochemical and cellular
readouts relative to compound <b>18</b>. Inhibitor <b>31</b> also displayed robust in vivo antitumor growth activity and dose-dependent
de-repression of EZH2 target genes
Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (<i>R</i>)‑5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroÂisoquinolin-1(2<i>H</i>)‑one (PF-06821497)
A new
series of lactam-derived EZH2 inhibitors was designed via
ligand-based and physicochemical-property-based strategies to address
metabolic stability and thermodynamic solubility issues associated
with previous lead compound <b>1</b>. The new inhibitors incorporated
an sp<sup>3</sup> hybridized carbon atom at the 7-position of the
lactam moiety present in lead compound <b>1</b> as a replacement
for a dimethylisoxazole group. This transformation enabled optimization
of the physicochemical properties and potency compared to compound <b>1</b>. Analysis of relationships between calculated log <i>D</i> (clogD) values and in vitro metabolic stability and permeability
parameters identified a clogD
range that afforded an increased probability of achieving favorable
ADME data in a single molecule. Compound <b>23a</b> exhibited
the best overlap of potency and pharmaceutical properties as well
as robust tumor growth inhibition in vivo and was therefore advanced
as a development candidate (PF-06821497). A crystal structure of <b>23a</b> in complex with the three-protein PRC2 complex enabled
understanding of the key structural features required for optimal
binding