Polymorphisms
in the region of the calmodulin-dependent kinase
isoform D (CaMK1D) gene are associated with increased incidence of
diabetes, with the most common polymorphism resulting in increased
recognition by transcription factors and increased protein expression.
While reducing CaMK1D expression has a potentially beneficial effect
on glucose processing in human hepatocytes, there are no known selective
inhibitors of CaMK1 kinases that can be used to validate or translate
these findings. Here we describe the development of a series of potent,
selective, and drug-like CaMK1 inhibitors that are able to provide
significant free target cover in mouse models and are therefore useful
as
in vivo
tool compounds. Our results show that
a lead compound from this series improves insulin sensitivity and
glucose control in the diet-induced obesity mouse model after both
acute and chronic administration, providing the first
in vivo
validation of CaMK1D as a target for diabetes therapeutics.
A parthenolide-derivative with favourable pharmacokinetic properties and good activity against drug-resistant chronic lymphocytic leukaemia is reported.
Some marketed antibiotics can cause mitochondria dysfunction via inhibition of the mitochondrial translation process. There is great interest in exploiting such effects within a cancer setting. To enhance accumulation of antibiotics within the mitochondria of cancer cells, and therefore delivery of a greater potency payload, a mitochondrial targeting group in the form of a triphenylphosphonium (TPP) cation was appended via an alkyl chain length consisting of 7 to 11 carbons to the ribosomal antibiotics azithromycin and doxycycline. Using MDA-MB-231 cells, the effects of each subseries on mitochondrial translation, mitochondrial bioenergetics, and cell viability are described.
A protocol for growing, extracting and derivatising parthenolide obtained from feverfew varieties is reported. Aminated parthenolide derivatives were prepared via 1,4-addition of primary or secondary amines utilising established and modified methods. The parthenolide derivatives’ drug-likeness properties were computed and they were screened for anti-leukaemic activity against the TP53-mutant, chemo-refractory, MEC1 chronic lymphocytic leukaemia (CLL) cell line. A screening cascade identified a small number of the most active compounds and their properties, including in vivo pharmacokinetics and in vitro hERG liability, were compared against DMAPT. This cascade culminated in the identification of a new compound with good anti CLL activity, with fewer drawbacks than some headline compounds from the literature and with utility against drug-resistant disease. Literature precedent and molecular docking studies support a multi-target-driven mode of action.<br>
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