ABSTRACT
The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) ß5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.
Subject(s)
Boron Compounds/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Proteasome Endopeptidase Complex/chemistry , Proteasome Inhibitors/pharmacology , Administration, Oral , Animals , Boron Compounds/administration & dosage , Boron Compounds/chemistry , Catalytic Domain , Humans , Malaria, Falciparum/enzymology , Malaria, Falciparum/parasitology , Mice , Mice, Inbred NOD , Mice, SCID , Models, Molecular , Plasmodium falciparum/enzymology , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/chemistryABSTRACT
Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.
Subject(s)
Membrane Proteins/agonists , Nucleotides, Cyclic/chemistry , Pyrimidines/chemistry , Administration, Intravenous , Animals , Binding Sites , Cell Line, Tumor , Half-Life , Humans , Immunotherapy , Membrane Proteins/metabolism , Mice , Molecular Docking Simulation , Neoplasms/pathology , Neoplasms/therapy , Nucleotides, Cyclic/metabolism , Nucleotides, Cyclic/therapeutic use , Phosphates/chemistry , Rats , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.
Subject(s)
Drug Discovery , Imidazoles/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazines/pharmacology , Pyrimidines/pharmacology , Checkpoint Kinase 1 , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A highly convergent second-generation synthesis of (+)-phorboxazole A has been achieved. Highlights of the synthetic approach include improved Petasis-Ferrier union/rearrangement conditions on a scale to assemble multigram quantities of the C(11-15) and C(22-26) cis-tetrahydropyrans inscribed with the phorboxazole architecture, a convenient method to prepare E- and Z-vinyl bromides from TMS-protected alkynes utilizing radical isomerization of Z-vinylsilanes, and a convergent late-stage Stille union to couple a fully elaborated C(1-28) macrocyclic iodide with a C(29-46) oxazole stannane side chain to establish the complete phorboxazole skeleton. The synthesis, achieved with a longest linear sequence of 24 steps, proceeded in 4.6% overall yield.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Magnetic Resonance Spectroscopy , Oxazoles/chemistry , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, InfraredABSTRACT
[structure: see text] A second generation total synthesis of the potent antitumor agent (+)-phorboxazole A (1) has been achieved. The cornerstone of this approach comprises a more convergent strategy, involving late-stage Stille union of a fully elaborated C(1-28) macrocycle with a C(29-46) side chain. The second generation synthesis entails the longest linear sequence of 24 steps, with an overall yield of 4.2%.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , Oxazoles/chemistryABSTRACT
[reaction: see text] A linear but concise synthetic approach toward the structurally related natural products myriaporone and tedanolide is reported. The route is highlighted by a stereoselective homoallenylboration and a regio- and chemoselective nitrile oxide cycloaddition. Installation of the (Z)-olefin completed the carbon skeleton of myriaporone 1.
