ABSTRACT
Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.
Subject(s)
Antineoplastic Agents , Neoplasms , Adult , Humans , Animals , Mice , Cyclin-Dependent Kinases , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Apoptosis , Cell Cycle Checkpoints , Disease Models, Animal , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Cyclin-Dependent Kinase 9 , Neoplasms/drug therapyABSTRACT
In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.
Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Clostridioides difficile/drug effects , Enterocolitis, Pseudomembranous/drug therapy , Heterocyclic Compounds, 2-Ring/pharmacology , Phenylurea Compounds/pharmacology , Pyrroles/pharmacology , Quinolines/pharmacology , Amino Acid Isomerases/genetics , Amino Acid Isomerases/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Clostridioides difficile/enzymology , Clostridioides difficile/genetics , Clostridioides difficile/growth & development , Drug Design , Enterocolitis, Pseudomembranous/microbiology , Enterocolitis, Pseudomembranous/mortality , Enterocolitis, Pseudomembranous/pathology , Female , Gene Expression , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Heterocyclic Compounds, 2-Ring/chemical synthesis , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Phenylurea Compounds/chemical synthesis , Pyrroles/chemical synthesis , Quinolines/chemical synthesis , Species Specificity , Structure-Activity Relationship , Survival AnalysisABSTRACT
A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.
Subject(s)
Antithrombins/chemical synthesis , Benzene/chemical synthesis , Drug Design , Thrombin/antagonists & inhibitors , Antithrombins/chemistry , Antithrombins/pharmacology , Benzene/chemistry , Benzene/pharmacology , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.
Subject(s)
Anticoagulants/pharmacology , Antithrombins/pharmacology , Drug Design , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Antithrombins/chemical synthesis , Antithrombins/chemistry , Antithrombins/pharmacokinetics , Biological Availability , Chlorides , Crystallography, X-Ray , Dogs , Ferric Compounds/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Macaca mulatta , Models, Molecular , Molecular Structure , Partial Thromboplastin Time , Rats , Structure-Activity Relationship , Thrombin/chemistry , Thrombin/metabolism , Trypsin/metabolismABSTRACT
Despite their relatively weak basicity, simple azoles, specifically imidazoles and aminothiazoles, can function as potent surrogates for the more basic amines (e.g., alkyl amines, amidines, guanidines, etc.) which are most often employed as the P1 ligand in the design of noncovalent small molecule inhibitors of thrombin.
Subject(s)
Azoles/pharmacology , Enzyme Inhibitors/pharmacology , Thrombin/antagonists & inhibitors , Azoles/chemistry , Drug Design , Ligands , Molecular Structure , Structure-Activity Relationship , Trypsin/drug effectsABSTRACT
Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the beta-alanine 3-substituent produced compounds that are potent and selective alpha(v)beta(3) antagonists and exhibit a range of physicochemical properties.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Pyrazines/chemistry , Pyridones/chemistry , Alanine/chemistry , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Molecular Mimicry , Oligopeptides , Protein Binding , Pyrazines/pharmacokinetics , Pyridones/pharmacokinetics , Radioimmunoassay , Structure-Activity RelationshipABSTRACT
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Thiadiazines/chemistry , Thiadiazines/pharmacology , Thrombin/antagonists & inhibitors , Acetamides/pharmacokinetics , Administration, Oral , Animals , Disease Models, Animal , Dogs , Ferric Compounds/toxicity , Humans , Models, Molecular , Pyridones/pharmacokinetics , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacokinetics , Sulfones/pharmacology , Thiadiazines/pharmacokinetics , Thrombosis/chemically induced , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacokinetics , Trypsin Inhibitors/pharmacologyABSTRACT
Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.
Subject(s)
Aza Compounds/chemistry , Aza Compounds/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Indoles/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Aza Compounds/pharmacokinetics , Dogs , Enzyme Inhibitors/pharmacokinetics , Humans , Indoles/pharmacokinetics , Models, Molecular , Partial Thromboplastin Time , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship , Substrate Specificity , Thrombin/metabolism , Trypsin/metabolismABSTRACT
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
