Optimizing drug-like properties of selective butyrylcholinesterase inhibitors for cognitive improvement: Enhancing aqueous solubility by disrupting molecular plane.

Most recently, worldwide interest in butyrylcholinesterase (BChE) as a potential target for treating Alzheimer's disease (AD) has increased. In this study, the previously obtained selective BChE inhibitors with benzimidazole-oxadiazole scaffold were further structurally modified to increase their aqueous solubility and pharmacokinetic (PK) characteristics. S16-1029 showed improved solubility (3280 µM, upgraded by 14 times) and PK parameters, including plasma exposure (AUC0-inf = 1729.95 ng/mL*h, upgraded by 2.6 times) and oral bioavailability (Fpo = 48.18%, upgraded by 2 times). S16-1029 also displayed weak or no inhibition against Cytochrome P450 (CYP450) and human ether a-go-go related gene (hERG) potassium channel. In vivo experiments on tissue distribution revealed that S16-1029 could cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). In vivo cognitive improvement efficacy and good in vitro target inhibitory activity (eqBChE IC50 = 11.35 ± 4.84 nM, hBChE IC50 = 48.1 ± 11.4 nM) were also assured. The neuroprotective effects against several AD pathology characteristics allowed S16-1029 to successfully protect the CNS of progressed AD patients. According to the findings of this study, altering molecular planarity might be a viable strategy for improving the drug-like property of CNS-treating drugs.

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer's Disease.

For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 µM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 µM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aß1-42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.

Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Butyrylcholinesterase-Activated Near-Infrared Fluorogenic Probe for In Vivo Theranostics of Alzheimer's Disease.

Butyrylcholinesterase (BChE) is a promising biomarker and effective therapeutic target for Alzheimer's disease (AD). Herein, we designed a BChE-activated near-infrared (NIR) probe, DTNP, which could be activated by BChE and inhibit its enzymatic activity. DTNP is composed of a cyclopropane moiety as the recognition unit, a NIR fluorophore hemicyanine as the NIR reporter, and a BChE inhibitor as the therapeutic unit. DTNP specifically binds BChE with high sensitivity and exhibits strong "turn-on" NIR fluorescence as well as nerve cell protection. In vivo imaging shows DTNP has favorable blood-brain barrier permeability and long-term tracking ability with preliminary competence in AD diagnosis. DTNP can significantly inhibit BChE activity, promote the release of ACh, and rescue learning deficits and cognitive impairment. Therefore, DTNP, the first reported and partially validated theranostic probe for the detection of BChE in AD, may provide a foundation and inspiration for imaging and therapy in AD.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Recent advances in targeting leucine-rich repeat kinase 2 as a potential strategy for the treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Several single gene mutations involved in PD have been identified such as leucine-rich repeat kinase 2 (LRRK2), the most common cause of sporadic and familial PD. Its mutations have attracted much attention to therapeutically targeting this kinase. To date, many compounds including small chemical molecules with diverse scaffolds and RNA agents have been developed with significant amelioration in preclinical PD models. Currently, five candidates, DNL201, DNL151, WXWH0226, NEU-723 and BIIB094, have advanced to clinical trials for PD treatment. In this review, we describe the structure, pathogenic mutations and the mechanism of LRRK2, and summarize the development of LRRK2 inhibitors in preclinical and clinical studies, trying to provide an insight into targeting LRRK2 for PD intervention in future.

Inhibition of Son of Sevenless Homologue 1 (SOS1): Promising therapeutic treatment for KRAS-mutant cancers.

Kristen rat sarcoma (KRAS) is one of the most common oncogenes in human cancers. As a guanine nucleotide exchange factor, Son of Sevenless Homologue 1 (SOS1) represents a potential therapeutic concept for the treatment of KRAS-mutant cancers because of its activation on KRAS and downstream signaling pathways. In this review, we provide a comprehensive overview of the structure, biological function, and regulation of SOS1. We also focus on the recent advances in SOS1 inhibitors and emphasize their binding modes, structure-activity relationships and pharmacological activities. We hope that this publication can provide a comprehensive compendium on the rational design of SOS1 inhibitors.

Identification of a Novel, Potent, and Orally Bioavailable Guanidine-Based SHP2 Allosteric Inhibitor from Virtual Screening and Rational Structural Optimization for the Treatment of KRAS Mutant Cancers.

Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a highly attractive therapeutic target for treating Kirsten rat sarcoma viral oncogene (KRAS) mutant cancers. In this work, a series of guanidine-based SHP2 allosteric inhibitors were discovered via virtual screening and rational structural optimization. Notably, lead compound 23 with potent SHP2 inhibitory activity (IC50 = 17.7 nM) effectively inhibited the proliferation, migration, and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, compound 23 featured great in vivo pharmacokinetic properties (AUCpo = 4320 nM·h; F = 66.3%) and exhibited significant antitumor efficacy in the MIA PaCa-2 xenograft mouse model. This demonstrates that compound 23 is a potential lead compound for the development of SHP2 allosteric inhibitors to treat KRAS mutant cancers. Moreover, these guanidine-based scaffolds may provide an opportunity to mitigate the potential safety risks of the alkyl amine motif predominately incorporated in current SHP2 allosteric inhibitors.

Design, Synthesis, and Proof of Concept of Balanced Dual Inhibitors of Butyrylcholinesterase (BChE) and Histone Deacetylase 6 (HDAC6) for the Treatment of Alzheimer's Disease.

Concomitant inhibition of butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) is supposed to be effective in the treatment of Alzheimer's disease (AD). Inspired by our previous efforts in designing BChE inhibitors, herein, selective BChE and HDAC6 dual inhibitors were successfully identified through the fusion of the core pharmacophoric moiety of BChE and HDAC6 inhibitors. After the structure-activity relationship (SAR) studies, two compounds (24g and 29a) were confirmed to have superior inhibitory activity against BChE (the IC50 against hBChE are 4.0 and 1.8 nM, respectively) and HDAC6 (the IC50 against HDAC6 are 8.9 and 71.0 nM, respectively). These two compounds showed prominently neuroprotective effects in vitro, potent reactive oxygen species (ROS) scavenging effects, and effective metal ion (Fe2+ and Cu2+) chelation. In addition, they exhibited pronounced inhibition of phosphorylated tau and a moderate immunomodulatory effect, with a lack of neurotoxicity at the cellular level. In vivo studies showed that both 24g and 29a ameliorated the cognitive impairment in an Aß1-42-induced mouse model at a low dosage (2.5 mg/kg). Our data demonstrated that BChE/HDAC6 dual inhibitors could establish the basis for a potential new symptomatic and disease-modifying strategy to treat AD.

The structural modification and biological evaluation of tetrahydrothienopyridine derivatives as selective BChE inhibitors.

A series of tetrahydrothienopyridine derivatives have been designed, synthesized, and evaluated as selective BChE inhibitors. Compounds were analyzed via HRMS, 1H NMR, and 13C NMR. The inhibitory effects were evaluated according to the method of Ellman et al. 6n was the most potent and selective inhibitor against BChE (eeAChE IC50 = 686.4 ± 478.6 µM, eqBChE IC50 = 10.5 ± 5.0 nM, SI = 6.5*104, hBChE IC50 = 32.5 ± 6.5 nM). Cell-based assays have confirmed the low neurotoxicity of 6a and 6n and their moderate neuroprotective effects. Compounds 6a and 6n provide novel chemical entities for the treatment of Alzheimer's disease.

Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment.

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.

Discovery of thiazole salt AChE inhibitors and development of thiamine disulfide prodrugs targeting the central nervous system.

The selective AChE inhibitor donepezil has been approved by the FDA as a first-line drug for the treatment of mild to moderate AD. However, many peripheral side effects were observed in patients taking donepezil. Our main objective here is to provide insight into the opportunities and challenges associated with development of AChE inhibitors with high brain exposure and low peripheral side effects. In this study, we have for the first time revealed a series of novel thiazole salt AChE inhibitors, which exhibit a nanomolar inhibitory effect on human AChE. We further developed thiamine disulfide prodrugs based on optimized thiazole salt AChE inhibitors, which are reduced in the brain to form thiazole salt AChE inhibitors. In vivo experiments have confirmed that the representative prodrug Tap4 (i.p., 10 mg/kg) can be converted into the thiazole salt AChE inhibitor Tat2 and shows high brain exposure, reaching 500 ng/g. Further, the inhibitory effect of the prodrug Tap4 on AChE is obviously stronger in the brain than that on intestinal AChE of ICR mice. Our study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.

Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC.

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

Regulation of beta-amyloid for the treatment of Alzheimer's disease: Research progress of therapeutic strategies and bioactive compounds.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is difficult to treat. Extracellular amyloid is the principal pathological criterion for the diagnosis of AD. Amyloid ß (Aß) interacts with various receptor molecules on the plasma membrane and mediates a series of signaling pathways that play a vital role in the occurrence and development of AD. Research on receptors that interact with Aß is currently ongoing. Overall, there are no effective medications to treat AD. In this review, we first discuss the importance of Aß in the pathogenesis of AD, then summarize the latest progress of Aß-related targets and compounds. Finally, we put forward the challenges and opportunities in the development of effective AD therapies.

Therapeutic potential of targeting kynurenine pathway in neurodegenerative diseases.

Kynurenine pathway (KP), the primary pathway of L-tryptophan (Trp) metabolism in mammals, contains several neuroactive metabolites such as kynurenic acid (KA) and quinolinic acid (QA). Its imbalance involved in aging and neurodegenerative diseases (NDs) has attracted much interest in therapeutically targeting KP enzymes and KP metabolite-associated receptors, especially kynurenine monooxygenase (KMO). Currently, many agents have been discovered with significant improvement in animal models but only one aryl hydrocarbon receptor (AHR) agonist 30 (laquinimod) has entered clinical trials for treating Huntington's disease (HD). In this review, we describe neuroactive KP metabolites, discuss the dysregulation of KP in aging and NDs and summarize the development of KP regulators in preclinical and clinical studies, offering an outlook of targeting KP for NDs treatment in future.

The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure-activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.

Design and Synthesis of Sulfonium Derivatives: A Novel Class of α-Glucosidase Inhibitors with Potent In Vivo Antihyperglycemic Activities.

We report the first attempt of double-spot structural modification on a side-chain moiety of sulfonium-type α-glucosidase inhibitors isolated from genus Salacia. A series of sulfonium salts with benzylidene acetal linkage at the C3' and C5' positions were designed and synthesized. In vitro enzyme inhibition evaluation showed that compounds with a strong electron-withdrawing group attached at the ortho position on the phenyl ring present stronger inhibitory activities. Notably, the most potent inhibitor 21b (1.0 mpk) can exhibit excellent hypoglycemic effects in mice, which can still compete with those of acarbose (20.0 mpk). Molecular docking of 21b demonstrated that besides conventional interacting patterns, the newly introduced benzylidene acetal moiety plays an important role in anchoring the whole molecule in a concave pocket of the enzyme. The successful identification of 21b as a lead compound for new drug discovery may provide a means for structure modification and diversification of the distinguished sulfonium-type α-glucosidase inhibitors.

Medicinal Prospects of Targeting Tyrosinase: A Feature Review.

Tyrosinase is a bifunctional polyphenol oxidase (PPO), catalyzing two oxidative reactions: monophenols to o-quinones (monophenolase activity) and o-diphenols to oquinones (diphenolase activity). As tyrosinase is the rate-limiting enzyme for the melanogenesis process, it is an attractive target for melanogenesis inhibition. Aiming at skin whitening, anticancer, Parkinson's disease (PD) treatment, antibacterial, fruit and vegetable preservation and other anti-pigmentation effect, medicinal chemists have exploited diverse tyrosinase inhibitors through various approaches. In addition to discovering inhibitors with novel scaffolds, good activity and high safety, researchers also focused on developing strategies for synergistic effects of multiple inhibitors and simultaneously regulating multiple targets to treat cancer or neurodegenerative diseases. This review focused on multiple natural and synthetic tyrosinase inhibitors, which could contribute to preventing fruit and vegetable browning, skin whitening, antibacterial, anticancer, Parkinson's Disease, etc.

Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the "gold standard" for breast cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative 27 (S19-1035) exhibits an IC50 value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast cancer treatment.