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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.

High performance liquid chromatography (HPLC) has seen a spectacular development during the last few years due to its rapidity and its high resolving power [l-7]. Recently, HPLC has also been applied to include biological macromolecules such as polynucleotides, polysaccharides and proteins [3-71. This paper describes the first use of bioaffinity supports (in contrast to normally used 'non-biological' stationary phases) to the resolution of biological macromolecules in combination with the technique of HPLC, and for this novel technique we suggest the term: high performance liquid affinity chromatography, HPLAC. Examples are given of enzyme and isozyme separations using an immobilised general ligand, AMP, and of albumins employing an immobilised immunosorbent, anti-serum albumin.

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