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Clinical Cancer Research : An Official... Jun 2024Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen...
PURPOSE
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC).
PATIENTS AND METHODS
Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%.
RESULTS
At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib.
CONCLUSIONS
Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.
Topics: Humans; Male; Benzimidazoles; Aged; Prostatic Neoplasms, Castration-Resistant; Aminopyridines; Middle Aged; Aged, 80 and over; Neoplasm Metastasis; Cyclin-Dependent Kinase 4; Treatment Outcome; Protein Kinase Inhibitors
PubMed: 38512117
DOI: 10.1158/1078-0432.CCR-23-3436 -
Molecules (Basel, Switzerland) Jun 2022(1) Background: Due to human activities, greenhouse gas (GHG) concentrations in the atmosphere are constantly rising, causing the greenhouse effect. Among GHGs, carbon...
(1) Background: Due to human activities, greenhouse gas (GHG) concentrations in the atmosphere are constantly rising, causing the greenhouse effect. Among GHGs, carbon dioxide (CO) is responsible for about two-thirds of the total energy imbalance which is the origin of the increase in the Earth's temperature. (2) Methods: In this field, we describe the development of periodic mesoporous organosilica nanoparticles (PMO NPs) used to capture and store CO present in the atmosphere. Several types of PMO NP (bis(triethoxysilyl)ethane (BTEE) as matrix, co-condensed with trialkoxysilylated aminopyridine (py) and trialkoxysilylated bipyridine (Etbipy and iPrbipy)) were synthesized by means of the sol-gel procedure, then characterized with different techniques (DLS, TEM, FTIR, BET). A systematic evaluation of CO adsorption was carried out at 298 K and 273 K, at low pressure. (3) Results: The best values of CO adsorption were obtained with 6% bipyridine: 1.045 mmol·g at 298 K and 2.26 mmol·g at 273 K. (4) Conclusions: The synthetized BTEE/aminopyridine or bipyridine PMO NPs showed significant results and could be promising for carbon capture and storage (CCS) application.
Topics: Adsorption; Aminopyridines; Carbon Dioxide; Humans; Nanoparticles; Porosity; Temperature
PubMed: 35807490
DOI: 10.3390/molecules27134245 -
Bioorganic & Medicinal Chemistry Letters Feb 2019An improved green synthesis of the E2F inhibitor HLM0066474 is described, using solvent-free and microwave irradiation conditions. The two enantiomers are separated...
An improved green synthesis of the E2F inhibitor HLM0066474 is described, using solvent-free and microwave irradiation conditions. The two enantiomers are separated using semi-preparative separation on Chiralpak ID and their absolute configuration is determined by vibrational circular dichroism (VCD) analysis. Biological evaluation of both enantiomers on E2F1 transcriptional activity reveals that the (+)-R, but not the (-)-S enantiomer is biologically active in repressing E2F1 transcriptional activity.
Topics: Aminopyridines; Circular Dichroism; Dose-Response Relationship, Drug; E2F1 Transcription Factor; HEK293 Cells; Humans; Hydroxyquinolines; Molecular Structure; Stereoisomerism; Structure-Activity Relationship
PubMed: 30578036
DOI: 10.1016/j.bmcl.2018.12.037 -
The Journal of Neuroscience : the... Aug 2011The contribution of neuronal dysfunction to neurodegeneration is studied in a mouse model of spinocerebellar ataxia type 1 (SCA1) displaying impaired motor performance... (Comparative Study)
Comparative Study
The contribution of neuronal dysfunction to neurodegeneration is studied in a mouse model of spinocerebellar ataxia type 1 (SCA1) displaying impaired motor performance ahead of loss or atrophy of cerebellar Purkinje cells. Presymptomatic SCA1 mice show a reduction in the firing rate of Purkinje cells (both in vivo and in slices) associated with a reduction in the efficiency of the main glutamatergic synapse onto Purkinje cells and with increased A-type potassium current. The A-type potassium channel Kv4.3 appears to be internalized in response to glutamatergic stimulation in Purkinje cells and accumulates in presymptomatic SCA1 mice. SCA1 mice are treated with aminopyridines, acting as potassium channel blockers to test whether the treatment could improve neuronal dysfunction, motor behavior, and neurodegeneration. In acutely treated young SCA1 mice, aminopyridines normalize the firing rate of Purkinje cells and the motor behavior of the animals. In chronically treated old SCA1 mice, 3,4-diaminopyridine improves the firing rate of Purkinje cells, the motor behavior of the animals, and partially protects against cell atrophy. Chronic treatment with 3,4-diaminopyridine is associated with increased cerebellar levels of BDNF, suggesting that partial protection against atrophy of Purkinje cells is possibly provided by an increased production of growth factors secondary to the reincrease in electrical activity. Our data suggest that aminopyridines might have symptomatic and/or neuroprotective beneficial effects in SCA1, that reduction in the firing rate of Purkinje cells can cause cerebellar ataxia, and that treatment of early neuronal dysfunction is relevant in neurodegenerative disorders such as SCA1.
Topics: Action Potentials; Aminopyridines; Animals; Conditioning, Eyelid; Disease Models, Animal; Mice; Mice, Transgenic; Motor Skills Disorders; Nerve Degeneration; Neuroprotective Agents; Spinocerebellar Ataxias; Time Factors
PubMed: 21849540
DOI: 10.1523/JNEUROSCI.0905-11.2011 -
Journal of Medicinal Chemistry Apr 2021In this study, we determined the crystal structure of an engineered human adenosine A receptor bound to a partial agonist and compared it to structures cocrystallized...
In this study, we determined the crystal structure of an engineered human adenosine A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.
Topics: Adenosine A2 Receptor Agonists; Aminopyridines; Animals; Binding Sites; CHO Cells; Cricetulus; Crystallography, X-Ray; Drug Inverse Agonism; Drug Partial Agonism; HEK293 Cells; Humans; Ligands; Molecular Docking Simulation; Protein Binding; Pyrimidines; Receptor, Adenosine A2A; Small Molecule Libraries
PubMed: 33764785
DOI: 10.1021/acs.jmedchem.0c01856 -
ChemMedChem Aug 2022The K 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions,...
The K 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine-induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. K 7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand-based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved K 7.2/3 channel opening activity, indicated by an up to 13-fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.
Topics: Aminopyridines; Carbamates; KCNQ Potassium Channels; Phenylenediamines
PubMed: 35687532
DOI: 10.1002/cmdc.202200262 -
Organic Letters Jun 2019Imines formed in situ from 2-aminopyridines and aldehydes undergo Rh(III)-catalyzed imidoyl C-H activation and coupling with diazo esters to give pyrido[1,2-...
Imines formed in situ from 2-aminopyridines and aldehydes undergo Rh(III)-catalyzed imidoyl C-H activation and coupling with diazo esters to give pyrido[1,2- a]pyrimidin-4-ones. Aromatic and enolizable aliphatic aldehydes were both effective substrates, and a broad range of functional groups were incorporated at different sites on the heterocyclic products. In addition, methoxy and dimethylamino functionalities could be directly installed on the pyrimidine ring by employing trimethyl orthoformate or N, N-dimethylformamide dimethyl acetal in place of the aldehyde, respectively.
Topics: Aldehydes; Aminopyridines; Azo Compounds; Catalysis; Esters; Imides; Molecular Structure; Pyridines; Pyrimidinones; Rhodium
PubMed: 30896175
DOI: 10.1021/acs.orglett.9b00779 -
European Journal of Drug Metabolism and... Mar 2022Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with anaplastic lymphoma kinase- (ALK) positive metastatic non-small cell lung cancer....
BACKGROUND AND OBJECTIVES
Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with anaplastic lymphoma kinase- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.
METHODS
Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.
RESULTS
A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration-time profile from time zero extrapolated to infinity (AUC) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort.
CONCLUSION
Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.
GOV IDENTIFIER
NCT03542305 (available May 31, 2018 on clinicaltrials.gov).
Topics: Adult; Aminopyridines; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Pyrazoles; Renal Insufficiency
PubMed: 35018553
DOI: 10.1007/s13318-021-00747-4 -
Journal of Experimental & Clinical... Nov 2021The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer...
BACKGROUND
The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer.
METHODS
The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining.
RESULTS
HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51.
CONCLUSIONS
Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the "off target" effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.
Topics: Aminopyridines; Animals; Autophagy; Humans; Hydroxychloroquine; Mice; Mice, Nude; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Zebrafish
PubMed: 34844627
DOI: 10.1186/s13046-021-02176-2 -
Journal of Medicinal Chemistry Apr 2011We report novel neuronal nitric oxide synthase (nNOS) inhibitors based on a symmetric double-headed aminopyridine scaffold. The inhibitors were designed from crystal...
We report novel neuronal nitric oxide synthase (nNOS) inhibitors based on a symmetric double-headed aminopyridine scaffold. The inhibitors were designed from crystal structures of leads 1 and 2 (Delker, S. L.; Ji, H.; Li, H.; Jamal, J.; Fang, J.; Xue, F.; Silverman, R. B.; Poulos, T. L. Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of cerebral palsy . J. Am. Chem. Soc. 2010, 132, 5437-5442) and synthesized using a highly efficient route. The best inhibitor, 3j, showed low nanomolar inhibitory potency and modest isoform selectivity. It also exhibited enhanced membrane permeability. Inhibitor 3j binds to both the substrate site and the pterin site in nNOS but only to the substrate site in eNOS. These compounds provide a basis for further development of novel, potent, isoform selective, and bioavailable inhibitors for nNOS.
Topics: Aminopyridines; Animals; Cattle; Cell Membrane Permeability; Drug Design; Enzyme Inhibitors; HEK293 Cells; Humans; Mice; Models, Molecular; Nitric Oxide Synthase Type I; Protein Conformation; Rats
PubMed: 21410186
DOI: 10.1021/jm101071n