ABSTRACT
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Animals , Chromatography, Liquid , Drug Design , Humans , Mass Spectrometry , Phenols/pharmacology , Protein Kinase Inhibitors/chemistry , Proton Magnetic Resonance Spectroscopy , Structure-Activity RelationshipABSTRACT
Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Picolinic Acids/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Amides/therapeutic use , Animals , Cell Line, Tumor , Halogenation , Humans , Leukemia, Myeloid, Acute/metabolism , Mice , Models, Molecular , Picolinic Acids/chemical synthesis , Picolinic Acids/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/metabolismABSTRACT
While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.
Subject(s)
Pyrazoles/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Animals , Cell Line , Crystallography, X-Ray , Humans , Male , Mice , Models, Molecular , Phosphorylation , Protein Conformation , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats, Sprague-Dawley , Signal Transduction , Structure-Activity Relationship , Y-Box-Binding Protein 1/metabolismABSTRACT
Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered.
ABSTRACT
2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.
Subject(s)
Benzoxazoles/chemistry , Protein Kinase Inhibitors/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Benzoxazoles/chemical synthesis , Benzoxazoles/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Structure, Tertiary , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Structure-Activity RelationshipABSTRACT
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.
