ABSTRACT
Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1. A preferred compound, 13b, had unprecedented sub-nanomolar JAK2 potency with an IC50 of 41â¯pM and a sub-nanomolar IC50 against HDAC6 of 200â¯pM. Binding models show a good fit into both JAK2 and HDAC6.
Subject(s)
Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Vorinostat/chemistry , Vorinostat/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Humans , Inhibitory Concentration 50 , Nitriles , Pyrimidines , Structure-Activity RelationshipABSTRACT
Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90). Although these enzymes have totally different functions they are related through inter-dependent pathways in the developing cancer cell. Synthesis of several complex multi-inhibiting ligands are presented along with initial enzyme inhibition data against 3 biological target classes of interest. A lead compound, 47, was discovered which had low micromolar activity for all 3 targets. Further development of these complex trispecific designed multiple ligands could result in a 'transient drug', an alternative combination therapy for treating cancer mediated via a single molecule.
Subject(s)
Amides/chemical synthesis , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Histone Deacetylase Inhibitors/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Amides/chemistry , Drug Design , Histone Deacetylase Inhibitors/chemistry , Nitriles , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Vorinostat/chemistryABSTRACT
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.
Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Animals , Cell Line, Tumor , Chromatography, Liquid , Histone Deacetylase Inhibitors/pharmacokinetics , Humans , Hydroxamic Acids/chemistry , Janus Kinase 1/chemistry , Janus Kinase 2/chemistry , Mice , Mice, Inbred BALB C , Models, Molecular , Nitriles , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/chemistry , Pyrimidines , Spectrum Analysis , VorinostatABSTRACT
Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases.
