A novel class of potent NaV1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse NaV1.7 inhibitory activity, which resulted in the discovery of N-aryl indoles. The introduction of the 3-methyl group is crucial for high NaV1.7 in vitro potency. The adjustment of lipophilicity led to the discovery of 2e. Compound 2e (DS43260857) demonstrated high in vitro potencies against both human and mouse NaV1.7 with high selectivity over NaV1.1, NaV1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.

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A targeted bibliographic search exposed the deficiencies within existing PROTAC preclinical pipelines, including missing, poor-quality data and technical limitations in the experimental assays. Several recommendations are proposed to improve the efficiency of preclinical platforms for PROTACs.

The activation of PINK1 by small molecules has emerged as a promising strategy in treating Parkinson’s disease (PD). Recent progress in this area has raised excitement around PINK1 activators as PD treatments, and herein we offer insight into these developments and their potential to deliver much needed novel PD treatments.

Parkinson’s Disease (PD) is a neurodegenerative movement disorder characterized by symptoms like resting tremor, rigidity, bradykinesia, and postural instability, mainly due to dopamine depletion and degeneration of dopaminergic neurons. Mitochondrial dysfunction plays a critical role in the disease’s progression, while amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease, is a fatal progressive neurodegenerative disease characterized by significant motor neuron loss in the primary motor cortex, brainstem, and spinal cord. This loss results in impaired movements such as breathing, leading to death within 2–5 years of diagnosis. Patients experience muscle weakness in the hands, arms, legs, and swallowing muscles and may require breathing aids. This Patent Highlight describes blends, such as microbiome compositions, that can be used to treat various diseases or conditions, particularly those affecting the nervous system, like neurodegenerative diseases (PD and ALS).

Provided herein are novel fused bicyclic heteroaryl compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD and processes for preparing such compounds.

This Viewpoint discusses the intersection of targeted protein degradation (TPD) technologies and psychedelic research. The resurgence in interest in psychedelics for treating mental disorders and the known genetic variability in responses require new strategies. TPD technologies might address this variability, modulating protein expressions based on genetic profiles. The discussion includes potential challenges in implementing TPD technologies in psychedelic research and potential strategies to address these issues. It considers lessons from COVID-19 research on genetic variability, proposing integration of TPD technologies into psychedelic research as a promising field despite these challenges, possibly leading to personalized treatments and improved patient outcomes.

4′-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis (Mtb) survival and virulence and therefore an attractive target for a tuberculosis therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of the amidinourea moiety present in the previously reported PptT inhibitor AU 8918 are reported. Although a designed 3,5-diamino imidazole unexpectedly adopted an undesired tautomeric form and was inactive, replacement of the amidinourea moiety afforded a series of active PptT inhibitors containing 2,6-diaminopyridine scaffolds.

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The KRASG12D mutation, frequently found in pancreatic cancer, is representative of various challenging cancers and is a crucial target for chemotherapy drug development. Researchers are exploring highly selective and potent small molecule inhibitors of KRASG12D to meet the needs of patients with this mutation. The Patent Highlight reveals novel compounds capable of inhibiting KRASG12D proteins, potentially useful in treating KRASG12D-associated diseases, including cancers.

We describe a phenotypic screening and optimization strategy to discover compounds that block intracellular checkpoint signaling in T-cells. We identified dual DGKα and ζ inhibitors notwithstanding the modest similarity between α and ζ relative to other DGK isoforms. Optimized compounds produced cytokine release and T-cell proliferation consistent with DGK inhibition and potentiated an immune response in human and mouse T-cells. Additionally, lead inhibitor BMS-502 demonstrated dose-dependent immune stimulation in the mouse OT-1 model, setting the stage for a drug discovery program.

The complexity of new therapeutics continues to increase and the timeline for the discovery of these therapeutics continues to shrink. This creates demand for new analytical techniques to facilitate quicker discovery and development of novel drugs. Mass spectrometry is one of the most prolific analytical techniques that has been applied across the entire drug discovery pipeline. New mass spectrometers and the associated methods for sampling have been introduced at a rate that keeps pace with new chemistries, therapeutic types, and screening practices used by modern drug hunters. This microperspective covers application and implementation of new mass spectrometry workflows that enable current and future efforts in screening and synthesis for drug discovery.

This viewpoint outlines the case for developing new chemical entities (NCEs) as racemates in infectious diseases and where both enantiomers and racemate retain similar on- and off-target activities as well as similar PK profiles. There are not major regulatory impediments for the development of a racemic drug, and minimizing the manufacturing costs becomes a particularly important objective when bringing an anti-infective therapeutic to the marketplace in the endemic settings of infectious diseases.

The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds 2 and 17a bound to Staphylococcus aureus DNA gyrase–DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the linker and the carboxylate of Asp83. Exploration of the structure–activity relationship within the series led to the identification of lead compound 18c, which showed potent broad-spectrum activity against a panel of MDR Gram-negative bacteria.

The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.

Provided herein are novel quinoline compounds as KRAS inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and processes for preparing such compounds.

The COVID-19 pandemic has highlighted the need for new antiviral approaches because many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a promising antiviral target because it plays a role in priming the spike protein before viral entry occurs for the most virulent variants. Further, TMPRSS2 has no established physiological role, thereby increasing its attractiveness as a target for antiviral agents. Here, we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we identify new noncovalent TMPRSS2 inhibitors that block SARS-CoV-2 infectivity in a cellular model. One such inhibitor, debrisoquine, has high ligand efficiency, and an initial structure–activity relationship study demonstrates that debrisoquine is a tractable hit compound for TMPRSS2.

Provided herein are novel dihydroorotate dehydrogenase (DHODH) inhibitors, pharmaceutical compositions, use of such compounds in treating acute myelogenous leukemia (AML), and processes for preparing such compounds.

Mitochondrial dysfunction has been attributed to many disease indications, including metabolic, cardiovascular, neoplastic, and neurodegenerative diseases. Dynamin related protein 1 (DRP1) is crucial in regulating mitochondrial fission and maintaining mitochondrial homeostasis. MiD49 is a dynamic peripheral protein receptor on the surface of the mitochondrial membrane that recruits DRP1 protein to induce mitochondrial binary fission. By targeting the protein–protein interaction of DRP1/MiD49, we have discovered a novel and potent allosteric DRP1 inhibitor that inhibits mitochondria fragmentation in vitro. X-ray cocrystal structure revealed that it locked the closed DRP1 conformation by induced dimerization.

Optimization of degrader properties is often a challenge due to their beyond-rule-of-5 nature. Given the paucity of known E3 ligases and the often-limited choice of ligands with varied chemical structures for a given protein target, degrader linkers represent the best position within the chimeric molecules to modify their overall physicochemical properties. In this work, a series of AT7519-based CDK9 degraders was assembled using click chemistry, facilitating the tuning of aqueous solubility and lipophilicity while retaining their linker type and molecular weight. Using chromatographic logD and kinetic solubility experiments, we show that degraders with similar chemical constitution but varied position of the embedded triazole demonstrate different lipophilicity and aqueous solubility properties. Overall, this work highlights the impact of triazole placement on linker composition through application of click chemistry for degrader synthesis and its ability to be used to promote the achievement of favorable physicochemical properties.