ABSTRACT
The powerful olefin metathesis reaction was employed for the construction of late-phase clinical agents SB1317 and SB1518. In both cases RCM seems to proceed only in the presence of an acid and to predominantly furnish trans isomers. In case of SB1518 it proceeded in the presence of acid HCl, while for SB1317, it mainly proceeds in the presence of TFA (trifluroacetic acid).
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Antineoplastic Agents/pharmacology , Bridged-Ring Compounds/pharmacology , Clinical Trials as Topic , Cyclization , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Janus Kinase 2/chemistry , Janus Kinase 2/metabolism , Lymphoma/drug therapy , Lymphoma/enzymology , Molecular Structure , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/enzymology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , StereoisomerismABSTRACT
Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemical synthesis , 3-Phosphoinositide-Dependent Protein Kinases , Animals , Antineoplastic Agents/pharmacology , Catalytic Domain , Computer Simulation , Drug Design , Humans , Kinetics , Ligands , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrimidinones/pharmacologyABSTRACT
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aurora Kinases , Drug Evaluation, Preclinical , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolismABSTRACT
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclin-Dependent Kinases/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Janus Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Computer Simulation , Dogs , Drug Screening Assays, Antitumor , Female , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Rats , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
Subject(s)
Antirheumatic Agents/chemical synthesis , Arthritis, Rheumatoid/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Cell Line , Cell Membrane Permeability , Collagen Type II , Dogs , Female , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Janus Kinase 2/physiology , Macaca mulatta , Male , Mice , Mice, Nude , Microsomes/metabolism , Models, Molecular , Rats , Signal Transduction/drug effects , Solubility , Stereoisomerism , Structure-Activity Relationship , TYK2 Kinase/antagonists & inhibitorsABSTRACT
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.