ABSTRACT
The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.
Subject(s)
Mitogen-Activated Protein Kinases/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , A549 Cells , Animals , Child , Child, Preschool , Female , Gain of Function Mutation/genetics , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , MAP Kinase Signaling System/physiology , Male , Mice , Mouse Embryonic Stem Cells , Mutation/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Signal Transduction , src Homology Domains/geneticsABSTRACT
Autoimmune and inflammatory diseases place a huge burden on the healthcare system. Small molecule (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: 1) protein kinases; 2) nucleic acid-sensing pathways; and 3) soluble ligands and receptors on cell surfaces. In this first part of the series, the focus is on kinase inhibitors that emerged between 2018 and 2020, and which exhibit increased target and tissue selectivity with the aim of increasing their therapeutic index.
Subject(s)
Autoimmune Diseases/drug therapy , Inflammation/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Small Molecule Libraries/pharmacology , Animals , Autoimmune Diseases/metabolism , Dose-Response Relationship, Drug , Humans , Inflammation/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemistry , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Chronic and dysregulated cytokine signaling plays an important role in the pathogenic development of many autoimmune and inflammatory diseases. Despite intrinsic challenges in the disruption of interactions between cytokines and cytokine receptors, many first-in-class small-molecule inhibitors have been discovered over the past few years. The third part of the digest series presents recent progress in identifying such inhibitors and highlights the application of novel research tools in the fields of structural biology, computational analysis, screening methods, biophysical/biochemical assays and medicinal chemistry strategy.
Subject(s)
Autoimmune Diseases/drug therapy , Cytokines/antagonists & inhibitors , Inflammation/drug therapy , Receptors, Cytokine/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Autoimmune Diseases/immunology , Cytokines/immunology , Humans , Inflammation/immunology , Molecular Structure , Receptors, Cytokine/immunology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistryABSTRACT
A mild Rh-catalyzed method for synthesis of cyclic unprotected N-Me and N-H 2,3-aminoethers using an olefin aziridination-aziridine ring-opening domino reaction has been developed. The method is readily applicable to the stereocontrolled synthesis of a variety of 2,3-disubstituted aminoether O-heterocyclic scaffolds, including tetrahydrofurans, tetrahydropyrans and chromanes.
Subject(s)
Ethers/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Nitrogen/chemistry , Chemistry Techniques, Synthetic , Hydrogen/chemistry , StereoisomerismABSTRACT
An efficient chemo- and regioselective N-vinylation of N-heteroarenes has been developed using vinylsulfonium salts. The reaction proceeded under mild and transition-metal-free conditions and consistently provided moderate to high yields of vinylation products with 100% E-stereoselectivity. This reaction is also highly chemoselective, and compatible with a variety of functional groups, such as -NHR, -NH2, -OH, -COOH, ester, etc.
ABSTRACT
A palladium-catalyzed difluoromethylation of a series of aryl chlorides and triflates under mild conditions was described. A variety of common functional groups were tolerated. In addition, by using this protocol, several drug molecules containing an aryl chloride unit were successfully difluoromethylated, thus enabling medicinal chemists to rapidly access novel drug derivatives with potentially improved properties via late-stage functionalization.
ABSTRACT
Fluoroalkylated quinoxlines with various groups were efficiently synthesized via a one-pot tandem Michael addition/azidation/cycloamination process. Under the mild and metal-free conditions, a bis-imine intermediate (4a) was detected and isolated for the first time. KI played a crucial role in this reaction. The mechanism was described.
ABSTRACT
A novel and efficient 2-step method for the functionalization of the C-H bond adjacent to the amino group of tetrahydropyridopyrimidine (THPP) is reported herein. The reaction features mild conditions and excellent tolerance of a wide range of functional groups. Moreover, this method is applicable to tetrahydroisoquinolone (THIQ), which provides a useful supplement to literature method. This method gives chemists a new tool to functionalize a C-H bond at late stage and may find applications in both synthetic organic and medicinal chemistry.
ABSTRACT
Convenient methods were developed for copper-mediated oxidative C-H activation of aminoquinoline benzamides. The reaction conditions can be tuned to give either hydroxylation or dimerization compounds as the major products efficiently. Preliminary mechanistic studies suggested that different coordination states of copper may lead to different reaction outcomes.
ABSTRACT
Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure-activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles.
Subject(s)
Amides/chemistry , Heterocyclic Compounds/chemistry , Mineralocorticoid Receptor Antagonists/pharmacology , Oxazoles/pharmacology , Receptors, Mineralocorticoid/metabolism , Animals , Dose-Response Relationship, Drug , Humans , Microsomes, Liver , Mineralocorticoid Receptor Antagonists/chemical synthesis , Mineralocorticoid Receptor Antagonists/chemistry , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure-activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.
Subject(s)
Mineralocorticoid Receptor Antagonists/chemistry , Oxazoles/chemistry , Receptors, Mineralocorticoid/metabolism , Animals , Binding Sites , Drug Evaluation, Preclinical , Half-Life , Humans , Microsomes/metabolism , Mineralocorticoid Receptor Antagonists/chemical synthesis , Mineralocorticoid Receptor Antagonists/pharmacokinetics , Molecular Docking Simulation , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Protein Structure, Tertiary , Rats , Receptors, Mineralocorticoid/chemistry , Structure-Activity RelationshipABSTRACT
Gold-catalyzed transformations allow efficient access to a wide scope of heterocyclic structures that serve as building blocks and pharmacophores in medicinal chemistry. Compared with other transition metal and Lewis acid catalysis, gold catalysis presents mechanistic divergence, excellent functional group tolerance and/or operational advantages. Emergent applications of gold catalysis have played a key role in the synthesis of biologically active molecules including a drug candidate.
Subject(s)
Gold/chemistry , Heterocyclic Compounds/chemistry , Catalysis , Chemistry, PharmaceuticalABSTRACT
Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , Cytochrome P-450 CYP3A/metabolism , Hepatitis B/drug therapy , Hepatitis B virus/metabolism , Hepatitis B, Chronic/drug therapy , Viral Core Proteins/metabolismABSTRACT
Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , Animals , Mice , Hepatitis B virus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Viral Core Proteins/metabolism , DNA, Viral , Hepatitis B/drug therapy , Hepatitis B, Chronic/drug therapyABSTRACT
Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.
Subject(s)
Benzimidazoles/pharmacology , Brain/metabolism , Carboxypeptidases/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Amides/chemistry , Animals , Biological Transport , Body Weight , Brain/drug effects , Disease Models, Animal , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Obesity/drug therapy , Pyrrolidines/chemistry , Time FactorsABSTRACT
A series of benzodihydroisofurans were discovered as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase (PrCP) inhibitors. The structure-activity relationship (SAR) is focused on improving PrCP activity and metabolic stability, and reducing plasma protein binding. In the established diet-induced obese (eDIO) mouse model, compound ent-3a displayed target engagement both in plasma and in brain. However, this compound failed to induce significant body weight loss in eDIO mice in a five-day study.
Subject(s)
Carboxypeptidases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Furans/chemistry , Furans/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Drug Stability , Enzyme Activation/drug effects , Furans/chemical synthesis , Humans , Mice , Mice, Obese , Molecular Structure , Structure-Activity RelationshipABSTRACT
As one of the leading causes of death from disease, cancer continues to pose a serious threat to human health globally. Despite the development of novel therapeutic regimens and drugs, the long-term survival of cancer patients is still very low, especially for those whose diagnosis is not caught early enough. Meanwhile, our understanding of tumorigenesis is still limited. Suitable research models are essential tools for exploring cancer mechanisms and treatments. Herein we review and compare several widely used in vitro and in vivo murine cancer models, including syngeneic tumor models, genetically engineered mouse models (GEMM), cell line-derived xenografts (CDX), patient-derived xenografts (PDX), conditionally reprogrammed (CR) cells, organoids, and MiniPDX. We will summarize the methodology and feasibility of various models in terms of their advantages and limitations in the application prospects for drug discovery and development and precision medicine.
Subject(s)
Neoplasms , Humans , Mice , Animals , Disease Models, Animal , Organoids , Precision Medicine/methods , HeterograftsABSTRACT
Chronic hepatitis B virus (HBV) infection is a worldwide disease that causes thousands of deaths per year. Currently, there is no therapeutic that can completely cure already infected HBV patients due to the inability of humans to eliminate covalently closed circular DNA (cccDNA), which serves as the template to (re)initiate an infection even after prolonged viral suppression. Through phenotypic screening, we discovered xanthone series hits as novel HBV cccDNA reducers, and subsequent structure optimization led to the identification of a lead compound with improved antiviral activity and pharmacokinetic profiles. A representative compound 59 demonstrated good potency and oral bioavailability with no cellular toxicity. In an HBVcircle mouse model, compound 59 showed excellent efficacy in significantly reducing HBV antigens, DNA, and intrahepatic cccDNA levels.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , DNA, Circular , DNA, Viral/genetics , Hepatitis B/drug therapy , Hepatitis B virus/genetics , Hepatitis B, Chronic/drug therapy , Humans , Mice , Virus ReplicationABSTRACT
A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.
Subject(s)
Amides , Benzimidazoles , Carboxypeptidases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors , Pyrrolidines , Amides/chemistry , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Disease Models, Animal , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.