Two voltage-gated calcium channel subtypes—CaV1.2 and CaV1.3—underlie the major L-type Ca2+ currents in the mammalian central nervous system. Owing to their high sequence homology, the two channel subtypes share similar pharmacological properties, and at high doses classic calcium channel blockers, such as dihydropyridines, phenylalkylamines and benzothiazepines, do not discriminate between the two channel subtypes. Recent progress in treating Parkinson’s disease (PD) was marked by the discovery of synthetic compound 8, which was reported to be a highly selective inhibitor of the CaV1.3 L-type calcium channels (LTCC). However, despite a previously reported IC50 of ~24 μM, in our hands inhibition of the full-length CaV1.342 by compound 8 at 50 μM reaches a maximum of 45%. Moreover, we find that the selectivity of compound 8 towards CaV1.3 relative to CaV1.2B15 channels is greatly influenced by the β-subunit type and its splice isoform variants.

Cytosolic phospholipase A2 (cPLA2) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA2. Several compounds were found to inhibit cPLA2 more strongly than arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor that is commonly used in the study of cPLA2-related neurodegenerative diseases. Subsequent experiments concluded that one of the inhibitors was found to be cPLA2-selective, non-cytotoxic, cell and brain penetrant and capable of reducing reactive oxygen species (ROS) and nitric oxide (NO) production in stimulated microglial cells. Computational studies were employed to understand how the compound interacts with cPLA2.

Arachidonic acid derivatives equipped with either one or two fluorescent groups attached to the tip of the alkyl chains were synthesized and shown to function as inhibitor and substrate probes of cPLA. The inhibitor probe was demonstrated to perform dual functions of inhibition and imaging while the substrate probe could be used for activity assay.

Traditional medicines provide a fertile ground to explore potent lead compounds, yet their transformation into modern drugs is fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. Herein we reveal that (Z)-(+)-isochaihulactone (1) exhibited significant inhibition against multiple-drug-resistant (MDR) cancer cell lines and mice xenografts. NMR spectroscopy showed that 1 resisted an off-target thiolate, thus indicating that 1 was a target covalent inhibitor (TCI). By identifying the pharmacophore of 1 (α,β-unsaturated moiety), a probe derived from 1 was designed and synthesized for TCI-oriented activity-based proteome profiling. By MS/MS and computer-guided molecular biology approaches, an affinity-driven Michael addition of the noncatalytic C247 residue of GAPDH was found to control the "ON/OFF" switch of apoptosis through non-canonically nuclear GAPDH translocation, which bypasses the common apoptosis-resistant route of MDR cancers.

Traditional medicines provide af ertile ground to explore potent lead compounds,y et their transformation into modern drugs is fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. Herein we reveal that (Z)-(+ +)-isochaihulactone (1)e xhibited significant inhibition against multiple-drug-resistant (MDR) cancer cell lines and mice xenografts.N MR spectroscopy showed that 1 resisted an off-target thiolate,thus indicating that 1 was at arget covalent inhibitor (TCI). By identifying the pharmacophore of 1 (a,b-unsaturated moiety), aprobe derived from 1 was designed and synthesized for TCI-oriented activitybased proteome profiling. By MS/MS and computer-guided molecular biology approaches,a na ffinity-driven Michael addition of the noncatalytic C247 residue of GAPDH was found to control the "ON/OFF" switch of apoptosis through non-canonically nuclear GAPDH translocation, which bypasses the common apoptosis-resistant route of MDR cancers.Traditional medicines are versatile compounds with avariety of biological effects and astructurally diverse set of scaffolds for lead discovery.N onetheless,al ack of knowledge of the mechanistic targets of ac ompound often impedes further structure-based drug design or therapeutic development. In this study,w ea imed to identify the mechanistic target of the active lignin 1 (a natural product isolated from the root of Bupleurum scorzonerifolium). Despite being an active inhibitor of several model cancer cell lines, [1,2] its drug-efficacy target remains unclear. Moreover,owing to the low extraction yields,i np revious studies ar acemic mixture of (Z)-isochaihulactone was used for characterization, [2] leaving the enantioselective cytotoxicity of each enantiomer ambiguous.Multiple-drug resistance (MDR) in prostate cancer has become asevere problem owing to limited available targeted agents.T he majority of the resistance is due to resurgence of the androgen receptor (AR) signaling,w hich is ap rimary culprit for therapeutic failure in incurable prostate cancers (PCa), especially in castration-resistant PCa (CRPC). [3] Firstline AR-directed therapies (ADTs;e .g., enzalutamide (Xtandi )a nd abiraterone (Zytiga )) depend on the druggability of the AR ligand binding domain (LBD);h owever, relapses emerge when affinity-related mutations (e.g., AR T877A in LNCaP) or complete loss of LBD (known as AR variants;e .g., AR V7 in 22Rv1) occur (models used in this study are listed in Table 1), which leads to MDR. The uncontrollable signaling of AR variants results in the constitutive expression of many anti-apoptosis-associated proteins,w hich thereby fuels the creation of av icious cycle of MDR to clinical-setting combination therapies. [4][5][6][7] Targeted covalent inhibitors [TCIs;Eq. (1)] are avaluable tool for drug discovery.C ompounds containing aw eak electrophilic warhead initially bind to the receptor protein so that it is positioned to subsequently form acovalent adduct with an oncatalytic nucleophile,t hus providing an extended dura...