Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.

Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.

In search of novel antitumor therapies. The natural product indirubin (1) is one of the class of indigo dyes, insoluble in aqueous systems, employed by mankind since the Bronze Age for textile coloring. In 1999 indirubin was reported to be a modest inhibitor of the enzyme CDK2, a key target in the ongoing search for novel antitumor therapies. With the guidance of X‐ray structures, indirubin was transformed to yield novel, soluble, almost colorless, highly potent CDK2 inhibitors that strongly inhibit the growth of the MCF7 tumor cell line in vitro.

ChemInform Abstract The o-(allyloxy)benzaldehydes (I) are coupled with the pyrazolones (II) or the isoxazolone (V) to form the allyloxybenzylidene derivatives (III) or (VI) which undergo intramolecular cycloaddition reaction, producing the hetero-fused benzopyranopyrans (IV) or (VII) with predominance of the corresponding cis-isomers. (Discussion of the transition states).

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