Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs)

A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this initial series led to the potent JAK2/JAK1 inhibitor CYT387 (N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide). Details of synthesis and SAR studies of these compounds are reported

Strand breakage by decay of DNA-bound ¹²⁴I provides a basis for combined PET imaging and Auger endoradiotherapy

<p><b>Purpose</b> DNA ligands labelled with ¹²⁵I induce cytotoxic DNA double-strand breaks (DSB), suggesting a potential for Auger endoradiotherapy. Since the 60-day half-life of ¹²⁵I is suboptimal for therapy, we have investigated another Auger-emitter ¹²⁴I, with shorter half-life (4.18 days), and the additional feature of positron-emission, enabling positron emission tomography (PET) imaging. The purpose of this study was to compare the two radionuclides on the basis of DNA DSB per decay.</p> <p><b>Materials and methods</b> Using a ¹²⁴I- (or ¹²⁵I)-labelled minor groove binding DNA ligand, we investigated DNA breakage using the plasmid DNA assay. Biodistribution of the conjugate of the labelled ligand with transferrin was investigated in nude mice bearing a K562 human lymphoma xenograft.</p> <p><b>Results</b> The probability of DSB per decay was 0.58 and 0.85 for ¹²⁴I and ¹²⁵I, respectively, confirming the therapeutic potential of the former. The crystal structure of the ligand DNA complex shows the iodine atom deep within the minor groove, consistent with the high efficiency of induced damage. Biodistribution studies, including PET imaging, showed distinctive results for the conjugate, compared to the free ligand and transferrin, consistent with receptor-mediated delivery of the ligand.</p> <p><b>Conclusions</b> Conjugation of ¹²⁴I-labelled DNA ligands to tumor targeting peptides provides a feasible strategy for Auger endoradiotherapy, with the advantage of monitoring tumor targeting by PET imaging.</p