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12 recordsLinked to original sources
PubMed2026

High-affinity, structure-validated and selective macrocyclic peptide tools for chemical biology studies of Huntingtin.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a Cytosine-Adenosine-Guanine (CAG) repeat expansion in the Huntingtin (HTT) gene, with no disease-modifying therapies currently available. The precise molecular function of the HTT protein is unclear, and the lack of selective chemical tools has limited functional studies. We have identified and characterized macrocyclic peptide binders targeting HTT. These binders exhibit low-nanomolar affinity in vitro and engage distinct HTT and HTT-HAP40 interfaces, as revealed by hydrogen-deuterium exchange mass spectrometry and cryoelectron microscopy. Chemoproteomics confirmed selective binding in cell extracts from wildtype but not HTT-null cell lines. HAP40 consistently and stoichiometrically copurified with HTT across cell lines, including with HTT variants containing different CAG repeat lengths, highlighting the broad presence of the HTT-HAP40 complex.

Huntingtin Protein↗
PubMed1975

On the active principles of the spurge family. III. Skin irritant and cocarcinogenic factors from the caper spurge.

The toxic and irritant principles of the seed oil and of the latex of the caper spurge (Euphorbia lathyris L.) were isolated together with several non irritants of similar chemical structure. From the seed oil two irritant Euphorbia factors L5 and L6 and from the latex a mixture of irritant Euphorbia factors were obtained. Euphorbia factor L5 was identified as 3-hexadecanoate of the new tetracyclic, poly-functional diterpene parent alcohol ingenol. Euphorbia factor L6 most probably is the 3-tetradeca-2,4,6,8,10-penta-enoic acid ester of ingenol. The mixture of Euphorbia factors was shown to contain esters of ingenol and of 16-hydroxy-ingenol, respectively, each containing a long chain unsaturated fatty acid, most probably in 3-position. The non irritants from the seed oil comprise ingenol-20-hexadecanoate (compound L4) and several esters of macrocyclic diterpenes of the new lathyrol type (compounds L1-L3, L8, and possibly L7). Compound L4 is a positional isomer of Euphorbia factor L5 and most probably an artefact formed during the isolation procedure. The macrocyclic diterpenes are of interest as possible intermediates in the biogenesis of tetracyclic diterpene parents of cocarcinogenic esters. The parent alcohols ingenol and 16-hydroxy-ingenol are inactive irritants. As compared to croton oil factor A1 (TPA), Euphorbia factor L5 exhibits about 1/10 of its irritant activity on the ear and about 1/10 of its cocarcinogenic activity on the back skin of mice. As an irritant Euphorbia factor L6 shows about 1/5 of the activity of A1. Structure/activity relationships of ingenol and phorbol esters and the possible role of cocarcinogens of plant origin as second order carcinogenic risk factors are discussed.

Animals↗
PubMed2026

Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.

Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.

Humans↗
PubMed1976

Synthesis of corrins and related macrocycles based on pyrrolic intermediates.

Intermediate in structure between porphyrins and corrins are the corroles and 1-methyltetradehydrocorrins. These ring systems, like the porphyrins, can be obtained by cyclization of linear tetrapyrrolic compounds, reactions which have been shown to proceed by orbital symmetry-allowed electrocyclic processes, and examples will be quoted. Thermolysis of nickel 1-methyltetradehydrocorrins causes a migration of the methyl group whereas similar treatment of nickel 1,19-dimethyltetradehydrocorrin salts yields porphyrin derivatives; the mechanisms of these transformations have been elucidated. Stepwise hydrogenation of metal tetradehydrocorrin salts (10 double bonds) yields a series of macrocycles containing 9, 8, 7, 6 and 5 double bonds and conditions necessary to obtain corrins have been established.

Chemical Phenomena↗
PubMed1979

Membrane effects of tumor promoters: stimulation of sugar uptake in mammalian cell cultures.

Phorbol esters stimulate 2-deoxy-D-glucose (DG) uptake in rodent and human cell cultures. The potent tumor promoting agent, 12-0-tetradecanoyl phorbol-13 acetate (TPA), induces a 12-fold stimulation in confluent 3T3 cells and 2.5-fold stimulation in HeLa cells. When a series of macrocyclic deterpenes are assayed, their relative potencies in stimulating DG uptake in 3T3 cells correlate with other known biologic effects of these compounds. On a molar basis, TPA is a much more potent stimulator of DG transport than insulin or epidermal growth factor. In HeLa cells, the ED50 value of the TPA effect is 0.2 nM. The increase in DG uptake occurs immediately after the addition of TPA, reaches a maximum at 90 minutes, persists for at least three hours after removal of TPA from the medium, and is temperature dependent. The stimulation is not inhibited by cycloheximide or actinomycin D. As in control cells, DG uptake in TPA treated cells is inhibited by p-hydroxymercuribenzoate, phyloridzin, cytochalasin B, and dexamethasone. Although the precise mechanism is not known, evidence is presented that the TPA stimulation of DG uptake is due to enhanced transport of the sugar rather than to effects on intracellular metabolism. The enhanced transport may be secondary to a more generalized change in membrane structure.

Biological Transport, Active↗
PubMed1978

Tumor-promoting phorbol esters inhibit binding of epidermal growth factor to cellular receptors.

Tumor-promoting phorbol esters and related plant macrocyclic diterpenes inhibit the binding of epidermal growth factor to its receptors on HeLa cells. This effect shows marked structural specificity and correlates with other biological effects of these compounds on mouse skin and in cell culture systems. The active compounds inhibited binding of 125I-labeled epidermal growth factor with a 50 per-cent effective dose in the range of 10(-8) to 10(-9) M. Inhibition appears to be due to a decrease in the number of available epidermal growth factor receptors rather than a change in receptor affinity. These results suggest that certain biologic effects of tumor promoters may result from alterations in the function of cell surface receptors involved in growth regulation.

Binding, Competitive↗
PubMed1978

Heterogeneity of murine erythroleukemia cells with respect to tumor promoter-mediated inhibition of cell differentiation.

Spontaneous and induced differentiation of murine erythroleukemia cells (strain 745A DS19 ) is reversibly inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent promoter of mouse skin carcinogenesis, and by other tumor-promoting macrocyclic plant diterpenes, but it is not by nonpromoting diterpenes. Twelve clones randomly isolated from this strain vary in their response to TPA. All clones are induced to differentiate by several compounds, the most potent of which is hexamethylene bisacetamide. In six clones TPA (100 ng/ml) caused greater than 90% inhibition of differentiation, as measured by the appearance of benzidine-reactive cells. In two clones cell differentiation was not inhibited by TPA even at concentrations as high as 1 microgram/ml. In four clones, differentiation was only partially inhibited (16 to 47%) by TPA. Clones resistant to TPA inhibition of differentiation were also resistant to structurally related tumor-promoting agents. The isolation of variant cell lines, sensitive and resistant to TPA, provides a tool for elucidating the mechanism of tumor promoter-mediated inhibition of cell differentiation.

Anesthetics↗
PubMed1976

Chemical reactivities of tetrapyrrole pigments: a comparison of experimentalbehaviour with the results of s.c.f.-pi-m.o. calculations.

Porphyrins are highly sigma-electron donating bases and very weak pi-acids. Hence they increase the electron density on central metal ions, e.g. iron, which leads to the specific reactivity of haem cytochromes, haemoglobin and oxidizing enzymes. The macrocyclic chlorin ligand behaves similarly but to a lesser degree which explains the comparably low oxidation potential of chlorophyll. Phlorins, oxophlorins, oxa- and aza-orphyrins, tetradehydrocorrins, corrins and biliverdins all produce metal complexes which have a similar geometry to that of metalloporphyrins, but their reactivity patterns are different. In contrast to the metalloporphyrins which undergo many fully reversible reactions, these compounds tend to irreversible addition and cleavage reactions. The tetrapyrrole ligands are stronger pi-acids than porphyrins. Results of some recent experimental work and pi-electron s.c.f. calculations are presented in support of these generalizations.

Chemical Phenomena↗
PubMed2026

Accelerate Your Science: Direct-to-Biology Strategies in Medicinal Chemistry.

Direct-to-biology (D2B) is a powerful strategy that accelerates early drug discovery. It enables compounds to be synthesized in miniaturized formats and evaluated directly as crude reaction mixtures. This bypasses the need for purification during the initial design-make-test cycle. Advances in robust synthetic methodologies, automation, reaction miniaturization, and biological screening have transformed D2B from a proof-of-concept approach into a versatile medicinal chemistry platform. This platform is applicable to fragment optimization, covalent ligands, macrocycles, proteolysis-targeting chimeras (PROTACs), molecular glues, and cellular phenotypic screening. This perspective focuses on the synthetic transformations, assay technologies, and platform implementations that drive modern D2B workflows. It emphasizes reaction robustness, assay compatibility, and practical implementation. Analysis of the current literature revealed that D2B is more governed by reaction reliability than synthetic diversity. Amide coupling and click chemistry dominate reported workflows, while more complex transformations remain underexplored. We discuss the complementary strengths and limitations of biochemical, biophysical, and cellular readouts, identify current bottlenecks in reaction scope and data management, and highlight emerging opportunities arising from reaction miniaturization, machine learning, automated experimentation, and advanced synthetic methodologies. Rather than replacing conventional medicinal chemistry, D2B fundamentally shifts experimental effort from purification toward early biological validation and is poised to become an integral component of future medicinal chemistry workflows.

Humans↗
PubMed2026

Macrocyclization of Broad-Spectrum Kinase Inhibitor Bosutinib Leads to Potent and Selective Quinoline-Based HIPK4 Inhibitor AZ137.

Homeodomain-interacting protein kinase 4 (HIPK4) remains an understudied member of the dark kinome. While genetic knockout studies suggest its involvement in spermiogenesis and cutaneous squamous cell carcinoma, whether these cellular functions can be recapitulated by pharmacological inhibition remains to be determined. These investigations are currently hampered by a lack of high-quality chemical tools. To address this, we employed a rational design strategy utilizing macrocyclization of a bosutinib-based scaffold. Systematic optimization led to the discovery of AZ137 (28e), a potent and selective HIPK4 inhibitor (IC50: 11 nM; cellular EC50: 76 nM). AZ137 exhibits exceptional selectivity across three comprehensive orthogonal panels, high solubility, and no detectable cytotoxicity. Its cellular activity was confirmed in cell-based assays of HIPK4-dependent F-actin remodeling. Together with a negative control compound, this probe set provides a foundational framework for validating HIPK4 as a therapeutic target and a high-quality resource to elucidate its roles in normal physiology and disease.

Quinolines↗
PubMed2026

Macrocyclization of Broad-Spectrum Kinase Inhibitor Bosutinib leads to Potent and Selective Quinoline-based HIPK4 Inhibitor AZ137.

Homeodomain-interacting protein kinase 4 (HIPK4) remains an understudied member of the dark kinome. While genetic knockout studies suggest roles for HIPK4 in spermiogenesis and cutaneous squamous cell carcinoma, whether these cellular functions can be recapitulated by pharmacological inhibition remains to be determined. However, such investigations have been hampered by a lack of high-quality chemical tools. To address this, we employed a rational design strategy utilizing macrocyclization of a bosutinib-based scaffold. Systematic optimization led to the discovery of AZ137 (28e), a potent and selective HIPK4 inhibitor (IC50 = 11 nM; cellular EC50 = 76 nM). AZ137 exhibits exceptional selectivity across three comprehensive orthogonal panels, high solubility, and no detectable cytotoxicity. Its cellular activity was confirmed in cell-based assays of HIPK4-dependent F-actin remodeling. Together with a negative control compound, this probe set provides a foundational framework for the validating HIPK4 as a therapeutic target and a high-quality resource to elucidate its roles in normal physiology and disease.

Journal Article↗
PubMed1979

Early intermediates in the biosynthesis of ansamycins. II. Isolation and identification of proansamycin B-M1 and protorifamycin i-M1.

Proansamycin B-M1 and protorifamycin I-M1 were isolated as minor compounds from fermentations of the protorifamycin I producing strain Nocardia mediterranei F 1/24, identified by means of chemical and spectroscopic methods and shown to be degradation products of the hypothetical proansamycin B postulated in part I of this series of papers and of protorifamycin I, respectively.

Anti-Bacterial Agents↗