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2.
J Med Chem ; 59(7): 3392-408, 2016 Apr 14.
Article in English | MEDLINE | ID: mdl-27003761

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Discovery , Indazoles/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Benzamides/administration & dosage , Benzamides/chemistry , Blood-Brain Barrier/drug effects , Blotting, Western , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Crystallization , Crystallography, X-Ray , Dogs , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Mice, SCID , Microsomes, Liver/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins/antagonists & inhibitors , Rats , Rats, Wistar , Receptor, trkA/antagonists & inhibitors , Receptor, trkB/antagonists & inhibitors , Receptor, trkC/antagonists & inhibitors , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
3.
ChemMedChem ; 10(2): 276-95, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25430902

ABSTRACT

Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R(1) and R(2) groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg(-1) ); it is therefore a suitable candidate for preclinical development.


Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/chemistry , Thiazoles/chemistry , Administration, Oral , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , MAP Kinase Kinase 1/genetics , MAP Kinase Kinase 1/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphorylation/drug effects , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Sulfonamides/therapeutic use , Sulfonamides/toxicity , Thiazoles/pharmacology , Thiazoles/therapeutic use , Thiazoles/toxicity , Transplantation, Heterologous
4.
Phys Med ; 30(6): 702-7, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24685182

ABSTRACT

PURPOSE: We set out to investigate the potential confounding effect of variable concentration of N-acetyl-l-aspartate (NAA) and Glutamate (Glu) on measurement of the brain oncometabolite 2-hydroxyglutarate (2HG) using a standard MRS protocol. This issue may arise due to spectral overlap at clinical magnetic field strengths and thus complicate the usage of 2HG as a putative biomarker of gliomas bearing mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes. METHODS: Spectra from 25 phantoms (50 mL falcon test tubes) containing a range of known concentrations of 2HG, NAA and Glu were acquired using a clinical 3 T scanner with a quadrature head coil, single-voxel point-resolved spectroscopy sequence with TE = 30 ms. Metabolite concentrations were estimated by linear combination analysis and a simulated basis set. RESULTS: NAA and Glu concentrations can have a significant confounding effect on 2HG measurements, whereby the negative changes in concentration of these metabolites typically observed in (peri)lesional areas can lead to under-estimation of 2HG concentration with respect to spectra acquired in presence of physiological levels of NAA and Glu. CONCLUSION: The confounding effect of NAA and Glu concentration changes needs to be considered: in patients, it may mask the presence of 2HG at low concentrations, however it is not expected to lead to false positives. 2HG data acquired using standard short echo-time MRS protocols should be considered with caution.


Subject(s)
Glutarates/metabolism , Phantoms, Imaging , Proton Magnetic Resonance Spectroscopy/instrumentation , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain/metabolism , Glioma/enzymology , Glioma/genetics , Glioma/metabolism , Glutamic Acid/metabolism , Humans , Isocitrate Dehydrogenase/genetics , Mutation
5.
ChemMedChem ; 2(4): 528-40, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17335099

ABSTRACT

Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.


Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Dose-Response Relationship, Drug , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Pyrimidines/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Vocalization, Animal/drug effects
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