Design and Synthesis of Ligand Efficient Dual Inhibitors of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Based on Ruxolitinib and Vorinostat

Abstract

Concomitant inhibition of multiple oncogenic pathways is a desirable goal in cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibitor vorinostat (2), leading to new molecules that are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1, 2, 3, 6, and 10 with IC50 values of less than 20 nM, is <100 nM potent against JAK2 and HDAC11, and is selective for the JAK family against a panel of 97 kinases. Broad cellular antiproliferative potency of 24 is supported by demonstration of JAK-STAT and HDAC pathway blockade in hematological cell lines. Methyl analogue 45 has an even more selective profile. This study provides new leads for assessment of JAK and HDAC pathway dual inhibiton achieved with a single molecule.

Next-generation of selective histone deacetylase inhibitors

“…Based on Ruxolitinib and Vorinostat, this group developed a new series of pyrazole substituted pyrrolopyrimidine based hydroxamates with HDAC and JAK inhibitory activities. 121 Finally, compound 48 with the optimal length of six carbons and methyl group, displayed single digit nanomolar potency against HDAC6. On this basis, Yao et al explored alternative attachment points for the hydroxamate bearing chain and the pyrazole substituent.…”

Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

“…For the preparation of ligands, 255 conformations were generated, and then docked into PI3Kα or HDAC1 by using Discovery Studio 2.1. Single inhibitor in PI3K and HDAC is according with the reported articles [42][43][44] in the key binding sites.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…into one molecule, to take advantage of the presence of large hydrophobic patches at the HDAC surface rim . Some encouraging results have been reported (Figure ), such as dual‐acting HDAC and topoisomerase II inhibitor 135 , triple HDAC and topoisomerase I/II inhibitor 136 , photoactivatable platinum(IV) complex cis , trans ‐[Pt(N 3 ) 2 (Sub) 2 (tBu 2 bpy)] ( 137 ) targeting genomic DNA and HDAC, dual‐acting estrogen receptor and HDAC inhibitor 138 , tamoxifen‐HDACI conjugate 139 and ethynyl‐estradiol‐HDACi conjugate 140 , chimeric 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGR)‐HDAC inhibitor 141 , dual‐acting androgen receptor (AR) and HDAC inhibitor 142 , stilbene‐SAHA chimeric molecule 143 , nitric oxide (NO)‐donor HDAC inhibitor 144 , chimeric c‐Src kinase and HDAC inhibitor 145 , and dual‐acting phosphodiesterase 5 (PDE5) and HDACs inhibitors 146 and 147 , JAK2‐HDAC dual inhibitor 148 (EY3238), JAK1‐HDAC dual inhibitor 149 , JAK2‐HDAC6 dual inhibitor 150 , PI3K‐HDAC dual inhibitors 151 , 152 , LSD1‐HDAC dual inhibitor 153 (Corin), IDO1‐HDAC dual inhibitor 154 and NAMPT‐HDAC dual inhibitor 155 , mammalian target of rapamycin‐HDAC dual inhibitor 156 . The design rationale for MTDLs is underpinned by deep insights derived from structural bioinformatics and structural biology.…”