SummaryThere is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. We describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the parasite, with good pharmacokinetic properties, and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
The antiplasmodial activity, DMPK
properties, and efficacy of a series of quinoline-4-carboxamides are
described. This series was identified from a phenotypic screen against
the blood stage of Plasmodium falciparum (3D7) and
displayed moderate potency but with suboptimal physicochemical properties
and poor microsomal stability. The screening hit (1,
EC50 = 120 nM) was optimized to lead molecules with low
nanomolar in vitro potency. Improvement of the pharmacokinetic profile
led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values
below 1 mg/kg when dosed orally for 4 days. The favorable potency,
selectivity, DMPK properties, and efficacy coupled with a novel mechanism
of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498)
to preclinical development.
The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 novel phorboids closely-related to tigilanol tiglate (EBC-46), a PKC-activating epoxytigliane showing promising clinical safety and efficacy for intratumoral treatment of cancers. While alkyl branching features of the C12-ester influenced potency, the 6,7-epoxide structural motif and position was critical to PKC activation in vitro. A subset of the 6,7-epoxytiglianes were efficacious against established tumors in mice; which generally correlated with in vitro activation of PKC. Importantly, epoxytiglianes without evidence of PKC activation showed limited antitumor efficacy. Taken together, these findings provide a strong rationale to reassess the role of PKC isoforms in cancer, and suggest in some situations their activation can be a promising strategy for anticancer drug discovery.
An efficient method for the copper-catalyzed N-arylation of hydroxylamines with aryl iodides is described. A variety of N- and O-functionalized hydroxylamines were transformed in good to excellent yield with a broad range of aryl coupling partners. Methods for the selective deprotection of either the N- or O-substituents for further functionalization are also described.
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