Practical Asymmetric Hydrogenation-Based Synthesis of a Class-Selective Histone Deacetylase Inhibitor

Two syntheses of the class-selective histone deacetylase inhibitor <b>1</b> are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording <i>trans</i>-<i>rac</i>-<b>5</b> and its resolution. In the second, asymmetric approach, the key steps were a highly selective asymmetric hydrogenation to produce the <i>cis</i>-(<i>S,S</i>)-3,4-disubstituted pyrrolidine <b>18</b> followed by an amide formation with simultaneous chiral inversion of the carboxy stereocenter to generate the key intermediate <i>trans</i>-(<i>R,S</i>)-3,4-disubstituted pyrrolidine <b>19</b>. The overall yield increased from ∼6% for the resolution approach to ∼26% for the enantioselective approach

Pharmacokinetic Optimization of Class-Selective Histone Deacetylase Inhibitors and Identification of Associated Candidate Predictive Biomarkers of Hepatocellular Carcinoma Tumor Response

Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead <b>5</b> (HDAC1 IC₅₀ = 60 nM, mouse CL = 39 mL/min/kg, mouse <i>F</i> = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated <b>5</b> in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies