ABSTRACT
Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Leukoencephalopathies , Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Mutation , Eukaryotic Initiation Factor-2B/genetics , Eukaryotic Initiation Factor-2B/metabolism , Brain/metabolism , Leukoencephalopathies/metabolismABSTRACT
Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Humans , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Leucine Zippers , MAP Kinase Kinase Kinases , Central Nervous System/metabolism , Brain/metabolism , Neurodegenerative Diseases/metabolismABSTRACT
USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Drug Discovery/methods , Ubiquitin-Specific Peptidase 7/antagonists & inhibitors , Ubiquitin-Specific Peptidase 7/chemistry , Administration, Oral , Animals , Cell Line, Tumor , Crystallography, X-Ray/methods , Humans , Mice , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Protein Structure, Tertiary , Ubiquitin-Specific Peptidase 7/metabolism , Xenograft Model Antitumor Assays/methodsABSTRACT
The communesin alkaloids are a diverse family of Penicillium-derived alkaloids. Their caged-polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian-derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.
Subject(s)
Alkaloids/chemical synthesis , Biological Products/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Hydrocarbons, Halogenated/chemical synthesis , Urochordata/chemistry , Alkaloids/chemistry , Animals , Biological Products/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Hydrocarbons, Halogenated/chemistry , Molecular Structure , StereoisomerismABSTRACT
We report the discovery, synthesis, and application of a new class of non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity.
Subject(s)
Allyl Compounds/chemistry , Ketones/chemistry , Palladium/chemistry , Alkylation , Catalysis , Ligands , Organophosphorus Compounds/chemistry , Oxidation-Reduction , StereoisomerismABSTRACT
Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in seven steps to demonstrate the synthetic utility of this transformation.
Subject(s)
Allyl Compounds/chemistry , Nucleosides/chemical synthesis , Palladium/chemistry , Pyrroles/chemistry , Pyrroles/chemical synthesis , Alkylation , Catalysis , Molecular Structure , Nucleosides/chemistry , StereoisomerismABSTRACT
Acetoxy Meldrum's acid can serve as a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation. The reaction of this nucleophile with various meso and racemic electrophiles afforded alkylated products in high yields and enantiopurities. These enantioenriched products are versatile intermediates that can be further functionalized using nitrogen- and oxygen-centered nucleophiles, affording versatile scaffolds for the synthesis of nucleoside analogues. These scaffolds were used to complete formal syntheses of the anti-HIV drugs carbovir, abacavir, and the antibiotic aristeromycin.
Subject(s)
Adenosine/analogs & derivatives , Allyl Compounds/chemical synthesis , Anti-HIV Agents/chemical synthesis , Dideoxynucleosides/chemical synthesis , Dioxanes/chemistry , Palladium/chemistry , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Alkylation , Allyl Compounds/chemistry , Allyl Compounds/pharmacology , Anions , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Catalysis , Combinatorial Chemistry Techniques , Dideoxynucleosides/chemistry , Dideoxynucleosides/pharmacology , Molecular Structure , StereoisomerismABSTRACT
We report that nitrogen heterocycles can serve as competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric alkylation of vinyl aziridines. The resulting alkylated products were obtained with high regio-, chemo-, and enantioselectivity. Both substituted 1H-pyrroles and 1H-indoles were successfully employed to give exclusively the branched N-alkylated products. The synthetic utility of this process was demonstrated by applying this method to the preparation of several medicinal chemistry lead compounds and bromopyrrole alkaloids including longamide B, longamide B methyl ester, hanishin, agesamides A and B, and cyclooroidin.
Subject(s)
Aziridines/chemistry , Heterocyclic Compounds/chemistry , Indoles/chemistry , Nitrogen/chemistry , Palladium/chemistry , Pyrroles/chemistry , Vinyl Compounds/chemistry , Catalysis , Drug Design , Molecular StructureABSTRACT
A concise, enantioselective synthesis of the potent aldose reductase inhibitor ranirestat (1) is reported. The synthesis was accomplished employing inexpensive, commercially available starting materials. A palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of malonate 4 was utilized as a key transformation to construct the tetrasubstituted chiral center in the target.
Subject(s)
Pyrazines/chemical synthesis , Spiro Compounds/chemical synthesis , Aldehyde Reductase/chemical synthesis , Aldehyde Reductase/chemistry , Molecular Structure , Pyrazines/chemistry , Spiro Compounds/chemistry , StereoisomerismABSTRACT
Several lower-rim perfluoroalkylated (fluorous) calix[4]arenes have been synthesized by O-alkylation of the parent calix[4]arene. The compounds are formed in the cone conformation. They are soluble in several fluorous solvents and show promise for use in sensing, selective extractions and other applications.
