ABSTRACT
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/metabolism , Animals , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Half-Life , Humans , Indoles/metabolism , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-pim-1/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , Indoles/metabolism , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Structure-Activity RelationshipABSTRACT
2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.
Subject(s)
Antineoplastic Agents/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/analogs & derivatives , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor/methods , Humans , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacologyABSTRACT
A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine was synthesized and found to have potent dual EGFR/HER2 kinase inhibitory activity. The structure-based drug design of this molecule as well as the kinase and cellular inhibition of HER2 kinase dependent cell lines will be discussed.
Subject(s)
Diamines/pharmacology , ErbB Receptors/metabolism , Oxadiazoles/pharmacology , Pyrimidines/pharmacology , Receptor, ErbB-2/metabolism , Cell Line , Diamines/chemical synthesis , Diamines/metabolism , Drug Design , ErbB Receptors/antagonists & inhibitors , HeLa Cells , Humans , Oxadiazoles/chemical synthesis , Oxadiazoles/metabolism , Protein Binding , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.
Subject(s)
Chemistry, Pharmaceutical/methods , ErbB Receptors/antagonists & inhibitors , Hydrazones/chemistry , Hydrazones/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Animals , Drug Design , Humans , Hydrazones/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Oximes/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , Oximes/pharmacology , Pyrimidines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Oximes/chemical synthesis , Oximes/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
Subject(s)
Antineoplastic Agents/therapeutic use , Blood-Brain Barrier/drug effects , Brain Neoplasms/drug therapy , Enzyme Inhibitors/therapeutic use , Morpholines/chemistry , Morpholines/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Blood-Brain Barrier/enzymology , Brain Neoplasms/enzymology , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Mice , Mice, Nude , Mice, SCID , Morpholines/pharmacology , Pyrimidines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Quinazolines/therapeutic use , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Xenograft Model Antitumor Assays/methodsABSTRACT
A novel series of 2,6-diamino-3-acylpyridines were designed and synthesized as cyclin-dependent kinase (CDK) inhibitors. The representative compounds 2r and 11 showed potent CDK1 and CDK2 inhibitory activities and inhibited cellular proliferation in HeLa, HCT116, and A375 tumor cells.