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Cardiovascular Toxicities Associated With Ibrutinib.
Salem JE, Manouchehri A, Bretagne M, Lebrun-Vignes B, Groarke JD, Johnson DB, Yang T, Reddy NM, Funck-Brentano C, Brown JR, Roden DM, Moslehi JJ
(2019) J Am Coll Cardiol 74: 1667-1678
MeSH Terms: Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Cardiovascular Diseases, Databases, Factual, Female, Humans, Male, Mortality, Pharmacovigilance, Pyrazoles, Pyrimidines, Retrospective Studies
Show Abstract · Added November 12, 2019
BACKGROUND - Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.
OBJECTIVES - The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.
METHODS - This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC (lower end of the IC 95% credibility interval) >0 is significant.
RESULTS - This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).
CONCLUSIONS - Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Discovery of a novel 3,4-dimethylcinnoline carboxamide M positive allosteric modulator (PAM) chemotype via scaffold hopping.
Temple KJ, Engers JL, Long MF, Gregro AR, Watson KJ, Chang S, Jenkins MT, Luscombe VB, Rodriguez AL, Niswender CM, Bridges TM, Conn PJ, Engers DW, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 126678
MeSH Terms: Allosteric Regulation, Amides, Azetidines, Benzene, Molecular Structure, Protein Binding, Pyrazines, Pyridines, Pyrimidines, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M PAM activity and improved clearance and protein binding profiles.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Insight on mutation-induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics simulations.
He MY, Li WK, Meiler J, Zheng QC, Zhang HX
(2019) Biopolymers 110: e23257
MeSH Terms: Adenosine Triphosphate, Anaplastic Lymphoma Kinase, Binding Sites, Drug Resistance, Neoplasm, Humans, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Neoplasms, Principal Component Analysis, Protein Kinase Inhibitors, Protein Structure, Tertiary, Pyrimidines, Sulfones
Show Abstract · Added March 21, 2020
Ceritinib, an advanced anaplastic lymphoma kinase (ALK) next-generation inhibitor, has been proved excellent antitumor activity in the treatment of ALK-associated cancers. However, the accumulation of acquired resistance mutations compromise the therapeutic efficacy of ceritinib. Despite abundant mutagenesis data, the structural determinants for reduced ceritinib binding in mutants remains elusive. Focusing on the G1123S and F1174C mutations, we applied molecular dynamics (MD) simulations to study possible reasons for drug resistance caused by these mutations. The MD simulations predict that the studied mutations allosterically impact the configurations of the ATP-binding pocket. An important hydrophobic cluster is identified that connects P-loop and the αC-helix, which has effects on stabilizing the conformation of ATP-binding pocket. It is suggested, in this study, that the G1123S and F1174C mutations can induce the conformational change of P-loop thereby causing the reduced ceritinib affinity and causing drug resistance.
© 2019 Wiley Periodicals, Inc.
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Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.
Brown JR, Moslehi J, Ewer MS, O'Brien SM, Ghia P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Coutre SE, Dilhuydy MS, Cramer P, Jaeger U, Dreyling M, Byrd JC, Treon S, Liu EY, Chang S, Bista A, Vempati R, Boornazian L, Valentino R, Reddy V, Mahler M, Yang H, Graef T, Burger JA
(2019) Br J Haematol 184: 558-569
MeSH Terms: Aged, Female, Hematologic Neoplasms, Hemorrhage, Humans, Incidence, Male, Middle Aged, Pyrazoles, Pyrimidines, Randomized Controlled Trials as Topic, Risk Factors, Time Factors
Show Abstract · Added December 13, 2018
Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.
© 2018 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores.
Childress ES, Wieting JM, Felts AS, Breiner MM, Long MF, Luscombe VB, Rodriguez AL, Cho HP, Blobaum AL, Niswender CM, Emmitte KA, Conn PJ, Lindsley CW
(2019) J Med Chem 62: 378-384
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Drug Evaluation, Preclinical, Half-Life, Humans, Inhibitory Concentration 50, Protein Isoforms, Pyrazoles, Pyridines, Pyrimidines, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
A scaffold hopping exercise from a monocyclic mGlu NAM with poor rodent PK led to two novel heterobicyclic series of mGlu NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu NAM potency, selectivity (versus mGlu and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.
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Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.
Felts AS, Rodriguez AL, Morrison RD, Blobaum AL, Byers FW, Daniels JS, Niswender CM, Conn PJ, Lindsley CW, Emmitte KA
(2018) Bioorg Med Chem Lett 28: 1679-1685
MeSH Terms: Allosteric Regulation, Animals, Dose-Response Relationship, Drug, Drug Discovery, Humans, Male, Molecular Structure, Pyrimidines, Quinolines, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.
Tang D, Fujinaga M, Hatori A, Zhang Y, Yamasaki T, Xie L, Mori W, Kumata K, Liu J, Manning HC, Huang G, Zhang MR
(2018) Eur J Med Chem 150: 1-8
MeSH Terms: Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Fluorine Radioisotopes, Humans, Inflammation, Ischemia, Male, Mice, Molecular Probes, Molecular Structure, Positron-Emission Tomography, Pyrazoles, Pyrimidines, Radioactive Tracers, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptors, GABA, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 22, 2018
Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [F]DPA-714. We evaluated the performance of [F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BP), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.
Copyright © 2018. Published by Elsevier Masson SAS.
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Cardiovascular care of patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI) therapy.
Barber MC, Mauro MJ, Moslehi J
(2017) Hematology Am Soc Hematol Educ Program 2017: 110-114
MeSH Terms: Aged, Dasatinib, Female, Fusion Proteins, bcr-abl, Humans, Hypertension, Pulmonary, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Protein Kinase Inhibitors, Pyridazines, Pyrimidines
Show Abstract · Added April 22, 2018
Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission." Importantly, later-generation BCR-ABL1 TKIs have been associated with CV complications. Dasatinib has been associated with pleural/pericardial effusions and pulmonary hypertension, whereas nilotinib and ponatinib have been linked to the development of vascular occlusive events. There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML. Nevertheless, optimal patient CV risk assessment needs to become a more central tenet of patient care in CML. We propose several practical considerations for the practicing oncologist relative to the CV health of patients with CML, especially those on chronic TKI therapy.
© 2016 by The American Society of Hematology. All rights reserved.
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Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels.
Zobeiri M, Chaudhary R, Datunashvili M, Heuermann RJ, Lüttjohann A, Narayanan V, Balfanz S, Meuth P, Chetkovich DM, Pape HC, Baumann A, van Luijtelaar G, Budde T
(2018) Brain Struct Funct 223: 1537-1564
MeSH Terms: Action Potentials, Adenine, Adenylyl Cyclase Inhibitors, Animals, Cardiovascular Agents, Cerebral Cortex, Cyclic AMP, Cyclic GMP, Female, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Neural Pathways, Peroxins, Pyrimidines, Sodium Channel Blockers, Tetrodotoxin, Thalamus, Thionucleotides
Show Abstract · Added April 2, 2019
Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I , in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K current, I , in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.
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MDM2 Antagonists Counteract Drug-Induced DNA Damage.
Vilgelm AE, Cobb P, Malikayil K, Flaherty D, Andrew Johnson C, Raman D, Saleh N, Higgins B, Vara BA, Johnston JN, Johnson DB, Kelley MC, Chen SC, Ayers GD, Richmond A
(2017) EBioMedicine 24: 43-55
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Azepines, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA Replication, HCT116 Cells, Humans, Imidazoles, Melanoma, Mice, Piperazines, Protein Binding, Proto-Oncogene Proteins c-mdm2, Pyrimidines, Pyrrolidines, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, para-Aminobenzoates
Show Abstract · Added June 20, 2018
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.
Copyright © 2017. Published by Elsevier B.V.
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