ABSTRACT
The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
Subject(s)
Centrosome/metabolism , Phthalazines/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Administration, Oral , Animals , Binding Sites , Caco-2 Cells , Centrosome/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , HeLa Cells , Humans , Microsomes/metabolism , Molecular Conformation , Molecular Dynamics Simulation , Phthalazines/administration & dosage , Phthalazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Protein Structure, Tertiary , Rats , Tankyrases/antagonists & inhibitors , Tankyrases/metabolismABSTRACT
Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
Subject(s)
Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , bcl-X Protein/antagonists & inhibitors , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-bcl-2/metabolism , Solubility , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , bcl-X Protein/metabolismABSTRACT
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
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.