No abstract

No abstract

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

No abstract

Microwave‐assisted condensation of 1,3,‐2‐dioxaphosphinane 2‐oxide (1), paraformaldehyde and secondary amines including 5‐ and 6‐membered N‐heterocycles at 55°C gave cyclic aminomethylphosphonates (2), whereas an analogous reaction involving dibenzo[c.e][1,2]oxaphosphinane 2‐oxide (3) resulted in the corresponding aminomethyl‐2‐(2′‐hydroxybiphenyl)phosphinic acids (4) as a consequence of a hydrolytic ring opening following the condensation. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:207–210, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20387