ABSTRACT
We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.
Subject(s)
Alkaloids , Antineoplastic Agents , Alkaloids/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Binding Sites , Biomarkers, Tumor/metabolism , Catalytic Domain , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Female , HSP90 Heat-Shock Proteins/metabolism , Humans , Isoxazoles/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Protein Binding/drug effects , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cell Cycle Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Cdc7 kinase has recently emerged as an attractive target for cancer therapy and low-molecular-weight inhibitors of Cdc7 kinase have been found to be effective in the inhibition of tumor growth in animal models. In this paper, we describe synthesis and structure-activity relationships of new 1H-pyrrolo[2,3-b]pyridine derivatives identified as inhibitors of Cdc7 kinase. Progress from (Z)-2-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one (1) to [(Z)-2-(benzylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-1,3-thiazol-4(5H)-one] (42), a potent ATP mimetic inhibitor of Cdc7 kinase with IC(50) value of 7 nM, is also reported.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Cell Cycle Proteins/chemistry , Cell Line , Humans , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/analogs & derivatives , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.