ABSTRACT
Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.
ABSTRACT
CVT-313 is a potent CDK2 inhibitor that was identified by screening a purine-analogue library and is currently in preclinical studies. Since this molecule has the potential to be developed as a CDK2 inhibitor for cancer therapy, the potency of CVT-313 to bind and stabilize CDK2 was evaluated, together with its ability to inhibit aberrant cell proliferation. CVT-313 increased the melting temperature of CDK2 by 7°C in thermal stabilization studies, thus indicating its protein-stabilizing effect. CVT-313 inhibited the growth of human lung carcinoma cell line A549 in a dose-dependent manner, with an IC50 of 1.2â µM, which is in line with the reported biochemical potency of 0.5â µM. To support the further chemical modification of CVT-313 and to improve its biochemical and cellular potency, a crystal structure was elucidated in order to understand the molecular interaction of CVT-313 and CDK2. The crystal structure of CDK2 bound to CVT-313 was determined to a resolution of 1.74â Å and clearly demonstrated that CVT-313 binds in the ATP-binding pocket, interacting with Leu83, Asp86 and Asp145 directly, and the binding was further stabilized by a water-mediated interaction with Asn132. Based on the crystal structure, further modifications of CVT-313 are proposed to provide additional interactions with CDK2 in the active site, which may significantly increase the biochemical and cellular potency of CVT-313.
Subject(s)
Adenosine Triphosphate/chemistry , Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase 2/chemistry , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , A549 Cells , Adenosine Triphosphate/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Cell Proliferation/drug effects , Cloning, Molecular , Crystallography, X-Ray , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/metabolism , Cyclic N-Oxides/pharmacology , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 2/metabolism , Dose-Response Relationship, Drug , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Indolizines/chemistry , Indolizines/metabolism , Indolizines/pharmacology , Models, Molecular , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Purines/chemistry , Purines/metabolism , Pyridinium Compounds/chemistry , Pyridinium Compounds/metabolism , Pyridinium Compounds/pharmacology , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Roscovitine/chemistry , Roscovitine/metabolism , Roscovitine/pharmacologyABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00287.].
ABSTRACT
The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.
ABSTRACT
Protein tyrosine phosphatase 1B (PTP1B) is a prototype non receptor cytoplasmic PTPase enzyme that has been implicated in regulation of insulin and leptin signaling pathways. Studies on PTP1B knockout mice and PTP1B antisense treated mice suggested that inhibition of PTP1B would be an effective strategy for the treatment of type II diabetes and obesity. Here we report the X-ray structure of PTP1B in complex with compound IN1834-146C (PDB ID 4I8N). The crystals belong to P3121 space group with cell dimensions (a = b = 87.89 Å, c = 103.68 Å) diffracted to 2.5 Å. The crystal structure contained one molecule of protein in the asymmetric unit and was solved by molecular replacement method. The compound engages both catalytic site and allosteric sites of PTP1B protein. We described the molecular interaction of the compound with the active site residues of PTP1B in this crystal structure report.
Subject(s)
Binding Sites/drug effects , Catalytic Domain/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/ultrastructure , Animals , Cloning, Molecular , Crystallography, X-Ray , Diabetes Mellitus, Type 2/therapy , Mice , Mice, Knockout , Obesity/therapy , Protein Tyrosine Phosphatase, Non-Receptor Type 1/geneticsABSTRACT
We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7 m and 7 n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7 k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif.