ABSTRACT
Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.
Subject(s)
Breast Neoplasms , Receptors, Estrogen , Mice , Humans , Animals , Female , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/pharmacology , Estrogen Antagonists/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor alpha/metabolism , Cell LineABSTRACT
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
Subject(s)
Cyclin-Dependent Kinase 9/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Animals , Apoptosis/drug effects , Binding Sites , Cell Line, Tumor , Cyclin-Dependent Kinase 9/metabolism , Dogs , Drug Evaluation, Preclinical , Half-Life , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/pathology , Humans , Mice , Molecular Docking Simulation , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridines/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Solubility , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
Subject(s)
Antineoplastic Agents/administration & dosage , Selective Estrogen Receptor Modulators/administration & dosage , Administration, Oral , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Biological Availability , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Cyclization , Drug Discovery , Female , Humans , Lipids/chemistry , Molecular Structure , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Wnt signaling is critical for development, cell proliferation and differentiation, and mutations in this pathway resulting in constitutive signaling have been implicated in various cancers. A pathway screen using a Wnt-dependent reporter identified a chemical series based on a 1,2,3-thiadiazole-5-carboxamide (TDZ) core with sub-micromolar potency. Herein we report a comprehensive mechanism-of-action deconvolution study toward identifying the efficacy target(s) and biological implication of this chemical series involving bottom-up quantitative chemoproteomics, cell biology, and biochemical methods. Through observing the effects of our probes on metabolism and performing confirmatory cellular and biochemical assays, we found that this chemical series inhibits ATP synthesis by uncoupling the mitochondrial potential. Affinity chemoproteomics experiments identified sarco(endo)plasmic reticulum Ca2+ -dependent ATPase (SERCA2) as a binding partner of the TDZ series, and subsequent validation studies suggest that the TDZ series can act as ionophores through SERCA2 toward Wnt pathway inhibition.
Subject(s)
Oxidative Phosphorylation/drug effects , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Thiadiazoles/pharmacology , Wnt Signaling Pathway/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
Negamycin is a natural product with antibacterial activity against a broad range of Gram-negative pathogens. Recent revelation of its ribosomal binding site and mode of inhibition has reinvigorated efforts to identify improved analogues with clinical potential. Translation-inhibitory potency and antimicrobial activity upon modification of different moieties of negamycin were in line with its observed ribosomal binding conformation, reaffirming stringent structural requirements for activity. However, substitutions on the N6 amine were tolerated and led to N6-(3-aminopropyl)-negamycin (31f), an analogue showing 4-fold improvement in antibacterial activity against key bacterial pathogens. This represents the most potent negamycin derivative to date and may be a stepping stone toward clinical development of this novel antibacterial class.
ABSTRACT
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/toxicity , Aniline Compounds/chemical synthesis , Aniline Compounds/toxicity , Cardiovascular System/drug effects , Enzyme Inhibitors/toxicity , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/toxicity , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guinea Pigs , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Myocytes, Cardiac/drug effects , RatsABSTRACT
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
ABSTRACT
In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.
ABSTRACT
3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.
Subject(s)
Amides/chemical synthesis , Aniline Compounds/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Amides/chemistry , Aniline Compounds/chemistry , Animals , Dogs , Heterocyclic Compounds, 2-Ring/chemistry , Mice , Molecular Structure , Protein Kinase Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Autoimmune Diseases/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Immunity/drug effects , Janus Kinase 2/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
