Authors: Morgan S Gadd, Andrea Testa, Xavier Lucas...

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

Topics: Amino Acid Sequence; Cell Cycle Proteins; Crystallography, X-Ray; Dipeptides; Elongin; Heterocyclic Compounds, 3-Ring; Humans; Models, Molecular; Multiprotein Complexes; Nuclear Proteins; Protein Binding; Protein Conformation; Proteolysis; Small Molecule Libraries; Structure-Activity Relationship; Thermodynamics; Transcription Factors; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein

PubMed: 28288108
DOI: 10.1038/nchembio.2329

Authors: Jo Ishizawa, Sarah F Zarabi, R Eric Davis...

The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.

Topics: Animals; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Endopeptidase Clp; Female; HCT116 Cells; HEK293 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Leukemia, Myeloid, Acute; Mice; Mitochondria; Models, Molecular; Point Mutation; Protein Conformation; Proteolysis; Pyridines; Pyrimidines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

PubMed: 31056398
DOI: 10.1016/j.ccell.2019.03.014

Authors: Michael Zengerle, Kwok-Ho Chan, Alessio Ciulli...

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.

Topics: Cell Cycle Proteins; Dipeptides; Drug Design; Gene Expression Regulation, Neoplastic; HeLa Cells; Heterocyclic Compounds, 3-Ring; Humans; Neoplasms; Nuclear Proteins; Proteolysis; Small Molecule Libraries; Transcription Factors; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein

PubMed: 26035625
DOI: 10.1021/acschembio.5b00216

Authors: Jing Lu, Yimin Qian, Martha Altieri...

BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.

Topics: Acetanilides; Adaptor Proteins, Signal Transducing; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Heterocyclic Compounds, 3-Ring; Humans; Nuclear Proteins; Peptide Hydrolases; Proto-Oncogene Proteins c-myc; Signal Transduction; Thalidomide; Transcription Factors; Triazoles; Ubiquitin-Protein Ligases

PubMed: 26051217
DOI: 10.1016/j.chembiol.2015.05.009

Review

Authors: Mohammad Aatif, Muhammad Asam Raza, Khadija Javed...

Heterocyclic compounds are considered as one of the major and most diverse family of organic compounds. Nowadays, the demand for these compounds is increasing day-by-day due to their enormous synthetic and biological applications. These heterocyclic compounds have unique antibacterial activity against various Gram-positive and Gram-negative bacterial strains. This review covers the antibacterial activity of different heterocyclic compounds with nitrogen moiety. Some of the derivatives of these compounds show excellent antibacterial activity, while others show reasonable activity against bacterial strains. This review paper aims to bring and discuss the detailed information on the antibacterial activity of various nitrogen-based heterocyclic compounds. It will be helpful for the future evolution of diseases to synthesize new and effective drug molecules.

PubMed: 36551407
DOI: 10.3390/antibiotics11121750

Review

Authors: N Jeelan Basha, S M Basavarajaiah, K Shyamsunder...

The chemistry of nitrogen-containing heterocyclic compound pyrrole and pyrrolidine has been a versatile field of study for a long time for its diverse biological and medicinal importance. Biomolecules such as chlorophyll, hemoglobin, myoglobin, and cytochrome are naturally occurring metal complexes of pyrrole. These metal complexes play a vital role in a living system like photosynthesis, oxygen carrier, as well storage, and redox cycling reactions. Apart from this, many medicinal drugs are derived from either pyrrole, pyrrolidine, or by its fused analogs. This review mainly focuses on the therapeutic potential of pyrrole, pyrrolidine, and its fused analogs, more specifically anticancer, anti-inflammatory, antiviral, and antituberculosis. Further, this review summarizes more recent reports on the pyrrole, pyrrolidine analogs, and their biological potential.

Topics: Anti-Inflammatory Agents; Antiviral Agents; Chlorophyll; Coordination Complexes; Cytochromes; Heterocyclic Compounds; Myoglobin; Nitrogen; Oxygen; Pyrroles; Pyrrolidines

PubMed: 35079946
DOI: 10.1007/s11030-022-10387-8

Review

Authors: Upare Abhay Atmaram, Selvaraj Mohana Roopan

The 5-membered oxadiazole and thiadiazole scaffolds are the most privileged and well-known heterocycles, being a common and essential feature of a variety of natural products and medicinal agents. These scaffolds take up the center position and are the core structural components of numerous drugs that belong to different categories. These include antimicrobial, anti-tubercular, anti-inflammatory, analgesic, antiepileptic, antiviral, and anticancer agents. In this review, we mostly talk about the isomers 1,2,4-oxadiazole and 1,3,4-thiadiazole because they have important pharmacological properties. This is partly because they are chemical and heat resistant, unlike other isomers, and they can be used as bio-isosteric replacements in drug design. We are reviewing the structural modifications of different oxadiazole and thiadiazole derivatives, more specifically, the anti-tubercular and anticancer pharmacological activities reported over the last 5 years, as we have undertaken this as a core area of research. This review article desires to do a thorough study and analysis of the recent progress made in the important biological isomers 1,2,4-oxadiazole and 1,3,4-thiadiazol. This will be a great place to start for future research. KEY POINTS: • Five-membered heterocyclic compound chemistry and biological activity recent survey. • Synthesis and pharmacological evolution of 1,2,4-oxadiazole and 1,3,4-thiadiazole are discussed in detail. • The value and significance of heterocyclic compounds in the field of drug designing are highlighted.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Oxadiazoles; Thiadiazoles

PubMed: 35562490
DOI: 10.1007/s00253-022-11969-0

Authors: Ivana Pibiri

Interest and research focusing on the design of novel pharmaceutical agents is always growing [...].

Topics: Drug Discovery; Humans; Heterocyclic Compounds

PubMed: 39273451
DOI: 10.3390/ijms25179503

Review

Authors: Carme Masdeu, Maria Fuertes, Endika Martin-Encinas...

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.

Topics: Alkaloids; Cell Survival; Coordination Complexes; Cycloaddition Reaction; Heterocyclic Compounds; Humans; Naphthyridines; Oxidation-Reduction

PubMed: 32752070
DOI: 10.3390/molecules25153508

Review

Authors: Nguyen Thi Chung, Vo Cong Dung, Dau Xuan Duc...

Benzimidazoles are a class of heterocyclic compounds in which a benzene ring is fused to the 4 and 5 positions of an imidazole ring. Benzimidazole refers to the parent compound, while benzimidazoles are a class of heterocyclic compounds having similar ring structures, but different substituents. Benzimidazole derivatives possess a wide range of bioactivities including antimicrobial, anthelmintic, antiviral, anticancer, and antihypertensive activities. Many compounds possessing a benzimidazole skeleton have been employed as drugs in the market. The application of benzimidazoles in other fields has also been documented. The synthesis of benzimidazole derivatives has attracted much attention from chemists and numerous articles on the synthesis of this class of heterocyclic compound have been reported over the years. The condensation between 1,2-benzenediamine and aldehydes has received intensive interest, while many novel methods have been developed. In this article, we will give a comprehensive review of studies on the synthesis of benzimidazole, which date back to 2013. We have also tried to describe reaction mechanisms as much as we can. The work might be useful for chemists who work in the synthesis of heterocycles or drug chemistry.

PubMed: 37942457
DOI: 10.1039/d3ra05960j