Highlights d SR-4835, a potent dual inhibitor of CDK12/CDK13, provokes TNBC cell death d CDK12/CDK13 inhibition/loss promotes cleavage at intronic polyadenylation sites d CDK12 inhibition causes a BRCAness phenotype by blocking homologous recombination d SR-4835 acts in synergy with DNA-damaging chemotherapy
Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.
AbstractThe in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.
The continued proliferation
of malaria throughout temperate and
tropical regions of the world has promoted a push for more efficacious
treatments to combat the disease. Unfortunately, more recent remedies
such as artemisinin combination therapies have been rendered less
effective due to developing parasite resistance, and new drugs are
required that target the parasite in the liver to support the disease
elimination efforts. Research was initiated to revisit antimalarials
developed in the 1940s and 1960s that were deemed unsuitable for use
as therapeutic agents as a result of poor understanding of both physicochemical
properties and parasitology. Structure–activity and structure–property
relationship studies were conducted to generate a set of compounds
with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with
a variety of phenyl moieties possessing various properties. Extensive
physicochemical evaluation of the quinolone series was carried out
to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67,
which possessed low-nanomolar EC50 values against W2 and
TM90-C2B as well as improved microsomal stability. Additionally, in
vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were
efficacious for the reduction of parasitemia at >99% after 6 days.
A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development.
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