ABSTRACT
The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Discovery , Imidazoles/therapeutic use , Lung Neoplasms/drug therapy , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazines/therapeutic use , Pyrimidines/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Apoptosis , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation , Drug Therapy, Combination , Female , Humans , Imidazoles/pharmacology , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Mice , Mice, Nude , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Pyrazines/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Anhydrouridines react with aliphatic amines to give N-alkyl isocytosines, but reported procedures often demand very long reaction times and can be low yielding, with narrow scope. A modified procedure for such reactions has been developed, using microwave irradiation, significantly reducing reaction time and allowing facile access to a diverse range of novel nucleosides on the gram scale. The method has been used to prepare a precursor to a novel analogue of lysidine, a naturally occurring iminonucleoside found in tRNA.
Subject(s)
Amines/chemistry , Cytosine/analogs & derivatives , Lysine/analogs & derivatives , Nucleosides/chemical synthesis , Pyrimidine Nucleosides/chemical synthesis , RNA, Transfer/chemistry , Cytosine/chemistry , Lysine/chemical synthesis , Lysine/chemistry , Molecular Structure , Nucleosides/chemistry , Pyrimidine Nucleosides/chemistry , RNA, Transfer/metabolismABSTRACT
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
Subject(s)
MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , Animals , Biological Availability , Cell Line, Tumor , Dogs , Drug Discovery , Humans , Methylation , Protein Kinase Inhibitors/pharmacokineticsABSTRACT
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
Subject(s)
Acrylamides/pharmacology , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/genetics , Chemistry Techniques, Synthetic , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/genetics , Female , Humans , Inhibitory Concentration 50 , Lung Neoplasms/genetics , Male , Mice , Middle Aged , Mutation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats, Inbred Strains , Xenograft Model Antitumor AssaysABSTRACT
A novel method for the synthesis of a wide range of 1,5-disubstituted 1,2-dihydro-1,2,4-triazol-3-ones is described. The key step involves a reaction between a dilithiated BOC-hydrazine and a N-alkoxycarbonylcarboximidothioate. A broad range of aryl and alkyl functional groups are tolerated, providing a versatile route for the synthesis of triazolones.
Subject(s)
Lithium/chemistry , Organometallic Compounds/chemistry , Triazoles/chemical synthesis , Molecular Structure , Triazoles/chemistryABSTRACT
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
Subject(s)
ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/genetics , Models, Molecular , Mutation , Structure-Activity RelationshipABSTRACT
A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Piperazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood Proteins/chemistry , Crystallography, X-Ray , Dogs , Drug Discovery , Humans , Inflammation/drug therapy , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Weight , Piperazines/chemistry , Piperazines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
A number of molecular recognition features have been exploited in structure-based design of selective Cathepsin inhibitors.
Subject(s)
Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemistry , Cathepsins/metabolism , Computer Simulation , Crystallography, X-Ray , Drug Design , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.
