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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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13 MeSH Terms
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, Sudhan DR, Guerrero-Zotano AL, Croessmann S, Guo Y, Ericsson PG, Lee KM, Nixon MJ, Schwarz LJ, Sanders ME, Dugger TC, Cruz MR, Behdad A, Cristofanilli M, Bardia A, O'Shaughnessy J, Nagy RJ, Lanman RB, Solovieff N, He W, Miller M, Su F, Shyr Y, Mayer IA, Balko JM, Arteaga CL
(2019) Nat Commun 10: 1373
MeSH Terms: Aminopyridines, Animals, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Circulating Tumor DNA, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Female, Fulvestrant, High-Throughput Nucleotide Sequencing, Humans, MCF-7 Cells, Mice, Mutation, Naphthalenes, Piperazines, Progression-Free Survival, Proportional Hazards Models, Protein Kinase Inhibitors, Purines, Pyrazoles, Pyridines, Quinolines, Quinoxalines, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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Surveying heterocycles as amide bioisosteres within a series of mGlu NAMs: Discovery of VU6019278.
Reed CW, Washecheck JP, Quitlag MC, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 1211-1214
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Hepatocytes, Heterocyclic Compounds, Inhibitory Concentration 50, Pyrazoles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu NAM chemotype led to the discovery of VU6019278, a potent mGlu NAM (IC = 501 nM, 6.3% L-AP Min) with favorable plasma protein binding (rat f = 0.10), low predicted hepatic clearance (rat CL = 27.7 mL/min/kg) and high CNS penetration (rat K = 4.9, K = 0.65).
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Glucose-mediated inhibition of calcium-activated potassium channels limits α-cell calcium influx and glucagon secretion.
Dickerson MT, Dadi PK, Altman MK, Verlage KR, Thorson AS, Jordan KL, Vierra NC, Amarnath G, Jacobson DA
(2019) Am J Physiol Endocrinol Metab 316: E646-E659
MeSH Terms: Alkanes, Animals, Apamin, Calcium, Calcium Channels, Calcium Channels, L-Type, Calcium Channels, P-Type, Calcium Channels, Q-Type, Endoplasmic Reticulum, Glucagon, Glucagon-Secreting Cells, Glucose, Mice, Mice, Transgenic, Patch-Clamp Techniques, Peptides, Potassium Channel Blockers, Potassium Channels, Calcium-Activated, Pyrazoles, Quinolinium Compounds
Show Abstract · Added February 13, 2019
Pancreatic α-cells exhibit oscillations in cytosolic Ca (Ca), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca oscillations have not been elucidated. As β-cell Ca oscillations are regulated in part by Ca-activated K (K) currents, this work investigated the role of K in α-cell Ca handling and GCG secretion. α-Cells displayed K currents that were dependent on Ca influx through L- and P/Q-type voltage-dependent Ca channels (VDCCs) as well as Ca released from endoplasmic reticulum stores. α-Cell K was decreased by small-conductance Ca-activated K (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca-activated K (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca-activated K (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of α-cell K with apamin depolarized membrane potential ( V) (3.8 ± 0.7 mV) and reduced action potential (AP) amplitude (10.4 ± 1.9 mV). Although apamin transiently increased Ca influx into α-cells at low glucose (42.9 ± 10.6%), sustained SK (38.5 ± 10.4%) or BK channel inhibition (31.0 ± 11.7%) decreased α-cell Ca influx. Total α-cell Ca was similarly reduced (28.3 ± 11.1%) following prolonged treatment with high glucose, but it was not decreased further by SK or BK channel inhibition. Consistent with reduced α-cell Ca following prolonged K inhibition, apamin decreased GCG secretion from mouse (20.4 ± 4.2%) and human (27.7 ± 13.1%) islets at low glucose. These data demonstrate that K activation provides a hyperpolarizing influence on α-cell V that sustains Ca entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when α-cell Ca is elevated during secretagogue stimulation, K activation helps to preserve GCG secretion.
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20 MeSH Terms
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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Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models.
Abney KK, Bubser M, Du Y, Kozek KA, Bridges TM, Linsdley CW, Daniels JS, Morrison RD, Wickman K, Hopkins CR, Jones CK, Weaver CD
(2019) ACS Chem Neurosci 10: 1294-1299
MeSH Terms: Analgesics, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Therapy, Combination, Formaldehyde, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, Hot Temperature, Humans, Male, Mice, Inbred C57BL, Morphine, Pain, Phenylurea Compounds, Pyrazoles
Show Abstract · Added April 10, 2019
G protein-gated inwardly rectifying potassium (GIRK) channels are potassium-selective ion channels. As their name suggests, GIRK channels are effectors of G G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of G-coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of opioid analgesics which act predominantly through G-coupled, opioid-activated GPCRs (e.g., μ-opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in pain pathways and as effectors of opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce analgesic efficacy and/or augment the analgesic efficacy morphine, an opioid receptor agonist capable of activating μ-opioid receptors as well as other opioid receptor subtypes. In the present study, we demonstrate that the small-molecule GIRK activator, VU0466551, has analgesic effects when dosed alone or in combination with submaximally effective doses of morphine.
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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 and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu positive allosteric modulators that mitigate CYP1A2 induction liability.
Engers DW, Bollinger SR, Engers JL, Panarese JD, Breiner MM, Gregro A, Blobaum AL, Bronson JJ, Wu YJ, Macor JE, Rodriguez AL, Zamorano R, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2018) Bioorg Med Chem Lett 28: 2641-2646
MeSH Terms: Allosteric Regulation, Animals, Antiparkinson Agents, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP1A2 Inducers, Drug Discovery, Enzyme Induction, Humans, Pyrazoles, Pyridines, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu PAMs, leading to 9i (hmGlu EC = 43 nM; AhR activation = 2.3-fold).
Copyright © 2018 Elsevier Ltd. All rights reserved.
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The discovery of VU0486846: steep SAR from a series of M PAMs based on a novel benzomorpholine core.
Bertron JL, Cho HP, Garcia-Barrantes PM, Panarese JD, Salovich JM, Nance KD, Engers DW, Rook JM, Blobaum AL, Niswender CM, Stauffer SR, Conn PJ, Lindsley CW
(2018) Bioorg Med Chem Lett 28: 2175-2179
MeSH Terms: Animals, CHO Cells, Cricetulus, Drug Discovery, Humans, Molecular Structure, Morpholines, Pyrazoles, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
Copyright © 2018 Elsevier Ltd. All rights reserved.
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A Novel M PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity.
Rook JM, Bertron JL, Cho HP, Garcia-Barrantes PM, Moran SP, Maksymetz JT, Nance KD, Dickerson JW, Remke DH, Chang S, Harp JM, Blobaum AL, Niswender CM, Jones CK, Stauffer SR, Conn PJ, Lindsley CW
(2018) ACS Chem Neurosci 9: 2274-2285
MeSH Terms: Allosteric Regulation, Animals, Antipsychotic Agents, CHO Cells, Cognition, Cognitive Dysfunction, Conditioning, Psychological, Cricetulus, Exploratory Behavior, Fear, Mice, Morpholines, Prefrontal Cortex, Pyrazoles, Rats, Risperidone, Seizures
Show Abstract · Added March 3, 2020
Selective activation of the M subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M PAM, VU0486846. VU0486846 possesses only weak agonist activity in M-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M PAM activity (EC > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.
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