Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.
Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found in tumors and CDK12 inhibition sensitize cancer cells to DNA-damaging reagents and DNA-repair inhibitors. This suggests that CDK12 inhibitors are potential therapeutics for cancer that may cause synthetic lethality. Here, we report the discovery of 3-benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective CDK12 inhibitors. Structure-activity relationship studies of a HTS hit, structure-based drug design, and conformation-oriented design using the Cambridge Structural Database afforded the optimized compound 2, which exhibited not only potent CDK12 (and CDK13) inhibitory activity and excellent selectivity but also good physicochemical properties. Furthermore, 2 inhibited the phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and induced growth inhibition in SK-BR-3 cells. Therefore, 2 represents an excellent chemical probe for functional studies of CDK12 and could be a promising lead compound for drug discovery.
With
over 200 million cases and close to half a million deaths
each year, malaria is a threat to global health, particularly in developing
countries. Plasmodium falciparum, the
parasite that causes the most severe form of the disease, has developed
resistance to all antimalarial drugs. Resistance to the first-line
antimalarial artemisinin and to artemisinin combination therapies
is widespread in Southeast Asia and is emerging in sub-Saharan Africa.
The P. falciparum proteasome is an
attractive antimalarial target because its inhibition kills the parasite
at multiple stages of its life cycle and restores artemisinin sensitivity
in parasites that have become resistant through mutation in Kelch
K13. Here, we detail our efforts to develop noncovalent, macrocyclic
peptide malaria proteasome inhibitors, guided by structural analysis
and pharmacokinetic properties, leading to a potent, species-selective,
metabolically stable inhibitor.
Treatment of tuberculosis (TB) currently
takes at least 6 months.
Latent Mycobacterium tuberculosis (Mtb)
is phenotypically tolerant to most anti-TB drugs. A key hypothesis
is that drugs that kill nonreplicating (NR) Mtb may shorten treatment
when used in combination with conventional drugs. The Mtb proteasome
(Mtb20S) could be such a target because its pharmacological inhibition
kills NR Mtb and its genetic deletion renders Mtb unable to persist
in mice. Here, we report a series of macrocyclic peptides that potently
and selectively target the Mtb20S over human proteasomes, including
macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity.
Inhibition of 20S within Mtb by 6 dose dependently led
to the accumulation of Pup-tagged GFP that is degradable but resistant
to depupylation and death of nonreplicating Mtb under nitrosative
stress. These results suggest that compounds of this class have the
potential to develop as anti-TB therapeutics.
The total syntheses of (+)-polygalolide A and (+)-polygalolide B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated through internal asymmetric induction from the stereocenter at C7 by a [Rh(2) (OAc)(4)]-catalyzed carbonyl ylide formation/intramolecular 1,3-dipolar cycloaddition sequence. The arylmethylidene moiety of these natural products was successfully installed by a Mukaiyama aldol-type reaction of a silyl enol ether with a dimethyl acetal, followed by elimination under basic conditions. We have also developed an alternative approach to the carbonyl ylide precursor based on a hetero-Michael reaction. This approach requires 18 steps, and the natural products were obtained in 9.8 and 9.3 % overall yields. Comparison of specific rotations of the synthetic materials and natural products suggests that polygalolides are biosynthesized in nearly racemic forms through a [5+2] cycloaddition between a fructose-derived oxypyrylium zwitterion with an isoprene derivative.
Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.
With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the Plasmodium proteasome is a promising strategy for antimalarial development.We recently reported a highly selective Plasmodium falciparum proteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeability of the series of macrocycles with other drug-like properties, we conducted further structure−activity relationship studies on a biphenyl ether-tethered macrocyclic scaffold. Extensive SAR studies around the P1, P3, and P5 groups and peptide backbone identified compound TDI-8414. TDI-8414 showed nanomolar antiparasitic activity, no toxicity to HepG2 cells, high selectivity against the Plasmodium proteasome over the human constitutive proteasome and immunoproteasome, improved solubility and PAMPA permeability, and enhanced metabolic stability in microsomes and plasma of both humans and mice.
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