ABSTRACT
Oncology clinical development programs have targeted the RAS/RAF/MEK/ERK signaling pathway with small molecule inhibitors for a variety of cancers during the past decades, and most therapies have shown limited or minimal success. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, most cancers have shown treatment resistance after several months of inhibitor usage, and reports indicate resistance is often associated with the reactivation of the MAPK signaling pathway. It is widely accepted that an effective MAPK therapy will have a significant impact on curtailing cancer growth and improving patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, an FDA-approved, effective anti-cancer ERK inhibitor has yet to be developed. Here, we present the design, optimization, and biological characterization of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate the phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. Our series of dual mechanism ERK1/2 inhibitors, in which we incorporated a triazolopyridinone core, may present potential benefits for enhancing efficacy and addressing the emergence of treatment resistance.
Subject(s)
MAP Kinase Signaling System , Neoplasms , Humans , Proto-Oncogene Proteins B-raf/metabolism , Neoplasms/drug therapy , Signal Transduction , Protein Kinase Inhibitors/chemistry , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinase Kinases/pharmacology , Mitogen-Activated Protein Kinase Kinases/therapeutic use , Mutation , Cell Line, TumorABSTRACT
Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Drug Discovery , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Area Under Curve , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Dogs , Drug Design , Gene Expression Regulation, Neoplastic/drug effects , Half-Life , Humans , Male , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Protein Conformation , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Xenograft Model Antitumor AssaysABSTRACT
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
ABSTRACT
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100â¯nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10â¯mpkâ¯=â¯0⯵Mâ¯h; F%â¯=â¯0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10â¯mpkâ¯=â¯26⯵Mâ¯h; F%â¯=â¯70).
Subject(s)
Antineoplastic Agents/pharmacology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrrolidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.
ABSTRACT
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.
Subject(s)
Extracellular Signal-Regulated MAP Kinases/genetics , MAP Kinase Kinase Kinases/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/genetics , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , Mutation , Neoplasms/drug therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
Protein kinase CK2 (CK2), a constitutively active serine/threonine kinase, is involved in a variety of roles essential to the maintenance of cellular homeostasis. Elevated levels of CK2 expression results in the dysregulation of key signaling pathways that regulate transcription, and has been implicated in cancer. The adenosine-5'-triphosphate-competitive inhibitor CX-4945 has been reported to show broad spectrum anti-proliferative activity in multiple cancer cell lines. Although the enzymatic IC(50) of CX-4945 has been reported, the thermodynamics and structural basis of binding to CK2α remained elusive. Presented here are the crystal structures of human CK2α in complex with CX-4945 and adenylyl phosphoramidate at 2.7 and 1.3 Å, respectively. Biophysical analysis of CX-4945 binding is also described. This data provides the structural rationale for the design of more potent inhibitors against this emerging cancer target.
Subject(s)
Casein Kinase II/chemistry , Models, Molecular , Naphthyridines/chemistry , Protein Structure, Tertiary , Adenylyl Imidodiphosphate/chemistry , Adenylyl Imidodiphosphate/metabolism , Binding Sites , Calorimetry , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Catalytic Domain , Circular Dichroism , Crystallography, X-Ray , Humans , Naphthyridines/metabolism , Naphthyridines/pharmacology , Phenazines , Protein Binding , Protein Subunits/antagonists & inhibitors , Protein Subunits/chemistry , Protein Subunits/metabolism , Temperature , ThermodynamicsABSTRACT
Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists.
Subject(s)
Neurokinin-1 Receptor Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , Area Under Curve , Chromatography, High Pressure Liquid , Gerbillinae , Half-Life , Piperidines/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious gamma-lactam series of selective NK(1) antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.
Subject(s)
Lactams/chemistry , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/chemistry , Administration, Oral , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Models, Chemical , Molecular Structure , Nitrogen/chemistry , Protein Binding , Structure-Activity Relationship , Substance P/chemistry , Urea/chemistry , VomitingABSTRACT
A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki Subject(s)
Cyclobutanes/pharmacology
, Neurokinin-1 Receptor Antagonists
, Serotonin Antagonists/chemistry
, Serotonin Antagonists/pharmacology
, Animals
, Binding Sites
, Cyclobutanes/chemistry
, Stereoisomerism
, Structure-Activity Relationship
ABSTRACT
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.
Subject(s)
Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Neurokinin-1 Receptor Antagonists , Urea/analogs & derivatives , Urea/pharmacology , Animals , Anti-Anxiety Agents/chemical synthesis , Benzyl Alcohols/chemistry , Crystallography, X-Ray , Drug Evaluation, Preclinical , Fluorine/chemistry , Gerbillinae , Models, Molecular , Molecular Structure , Motor Activity/drug effects , Structure-Activity Relationship , Urea/chemical synthesisABSTRACT
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.
Subject(s)
Neurokinin-1 Receptor Antagonists , Urea/analogs & derivatives , Animals , Biological Availability , Dose-Response Relationship, Drug , Gerbillinae , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Motor Activity/drug effects , Protein Binding , Rats , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
[structure: see text] A highly efficient and practical synthesis of 4,4-Disubstituted-2-Imidazolidinones utilizing a "self-reproduction of the center of chirality" strategy is described.
ABSTRACT
By employing a stereosimplification approach, a thorough SAR exploration of the piperidine region of Sch 206272 was possible through a practical and efficient synthesis of substituted cyclic ureas. This SAR study led to the identification of a benzimidazolinone series of compounds which display single digit nanomolar NK(1)/NK(2) affinity and near micromolar binding for the NK(3) receptor.