ACS Medicinal Chemistry Letters最新文献

Pin1 (peptidyl-prolyl cis–trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of Pin1 with a covalent inhibitor is a potential strategy for developing anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward Pin1, which were validated for their covalent binding to Cys113 of Pin1 by X-ray cocrystal structures of compounds 4a (IC₅₀ = 11.55 μM) and 6a (IC₅₀ = 3.15 μM). This work provided a new approach for covalent inhibition of Pin1 by taking advantage of the 2-chloro-5-nitropyrimidine as the electrophilic warhead, which might benefit the discovery of potent and drug-like Pin1 inhibitors.

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of Pin1 with a covalent inhibitor is a potential strategy for developing anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward Pin1, which were validated for their covalent binding to Cys113 of Pin1 by X-ray cocrystal structures of compounds 4a (IC₅₀ = 11.55 μM) and 6a (IC₅₀ = 3.15 μM). This work provided a new approach for covalent inhibition of Pin1 by taking advantage of the 2-chloro-5-nitropyrimidine as the electrophilic warhead, which might benefit the discovery of potent and drug-like Pin1 inhibitors.

Provided herein are novel ergoline compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mood disorders such as depressive disorders and bipolar disorders, and processes for preparing such compounds.

The head-to-tail cyclic peptide cyclo[Arg-Lys-Pro-Tyr-Tle-Leu] (peptide 1, where Tle is l-tert-Leu) has previously been reported to bind to neurotensin receptor 1 (NTS1) (pKi = 5.97). Upon seeking to reproduce this finding, we found that peptide 1 did not have a measurable affinity for NTS1. However, a semipurified preparation of peptide 1 appeared to bind to NTS1 with pKi = 5.83 ± 0.25 SEM. Resynthesis of peptide 1 using a shifted peptide register gave linear and cyclic forms of peptide 1 that were both unable to bind to NTS1. We observe that the previously reported activity of peptide 1 may be due to the presence of high affinity linear contaminants. Approximately 3% contamination with the linear variant would explain the apparent binding of the semipure peptide 1 sample. From this study, we propose that shifting the peptide register during synthesis as a strategy to minimize the presence of potent precursor contaminants.

The head-to-tail cyclic peptide cyclo[Arg-Lys-Pro-Tyr-Tle-Leu] (peptide 1, where Tle is l-tert-Leu) has previously been reported to bind to neurotensin receptor 1 (NTS1) (pKi = 5.97). Upon seeking to reproduce this finding, we found that peptide 1 did not have a measurable affinity for NTS1. However, a semipurified preparation of peptide 1 appeared to bind to NTS1 with pKi = 5.83 ± 0.25 SEM. Resynthesis of peptide 1 using a shifted peptide register gave linear and cyclic forms of peptide 1 that were both unable to bind to NTS1. We observe that the previously reported activity of peptide 1 may be due to the presence of high affinity linear contaminants. Approximately 3% contamination with the linear variant would explain the apparent binding of the semipure peptide 1 sample. From this study, we propose that shifting the peptide register during synthesis as a strategy to minimize the presence of potent precursor contaminants.

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.

Recent advancements in pharmaceutical research have focused on developing novel psychoactive compounds and receptor modulators that enhance therapeutic outcomes while minimizing adverse effects. This Patent Highlight examines three innovative approaches: (1) transmucosal delivery of dephosphorylated psychoactive alkaloids, (2) nonhallucinogenic serotonin receptor modulators, and (3) ergoline analogues designed for treating neurological disorders. These innovations offer breakthroughs in drug delivery, receptor targeting, and structural modifications, aiming to address challenges in the treatment of mood disorders, neurological diseases, and chronic pain while improving bioavailability and reducing side effects and hallucinogenic properties.

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody–drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure–activity relationship studies guided by structure-based drug design are described.

Innovations in pharmaceutical science drive new treatment approaches for cancer and brain injury. This Patent Highlight reviews findings from three patents focused on kinase inhibition in cancer therapy and using biomarkers to assess brain injury. By targeting key enzymes such as AKT1 and diacylglycerol kinase alpha (DGKα), these innovations offer new strategies for cancer treatment, particularly in cases of resistance to conventional therapies. In parallel, advances in biomarker-based diagnostics provide a more sensitive means of detecting traumatic brain injuries (TBI). Together, these breakthroughs hold promise for improving outcomes in oncology and neurology.

This Patent Highlight explores recent innovations in neuroscience and neurotechnology, particularly in brain monitoring and stimulation. It examines four essential patents: novel psychoplastogens for neuronal growth, techniques for transferring emotional states, and advanced systems for self-guided neural diagnostics and treatment. The discussion extends to deep brain stimulation (DBS) for motor and memory disorders, enhanced brain function monitoring through electroencephalography (EEG), and the role of artificial intelligence in personalizing treatment strategies. These advancements represent a pivotal development in neurotechnology, introducing innovative methodologies for elucidating neurological mechanisms, addressing psychiatric disorders, and augmenting cognitive and neural function.