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Archiv Der Pharmazie Oct 2023Histone deacetylase (HDAC) inhibitors are well-established multifaceted bioactive agents against tumors and neurodegenerative disorders. Pyrimidine and its fused and... (Review)
Review
Histone deacetylase (HDAC) inhibitors are well-established multifaceted bioactive agents against tumors and neurodegenerative disorders. Pyrimidine and its fused and substituted derivatives were employed as a surface recognition moiety of HDAC inhibitors. De facto, the literature was loaded with different success stories of pyrimidine-based HDAC inhibitors that garnered much interest. Provoked by our continuous interest in HDAC inhibitors, we summarized and elaborated on the successful harnessing of the pyrimidine scaffold in this regard. Furthermore, we dissect our perspective that may guide medicinal chemists for an effective future design of more active chemotherapeutic agents with potential clinical applications.
Topics: Histone Deacetylase Inhibitors; Antineoplastic Agents; Structure-Activity Relationship; Histone Deacetylases; Cell Proliferation; Pyrimidines; Histone Deacetylase 1
PubMed: 37462396
DOI: 10.1002/ardp.202300208 -
Future Medicinal Chemistry Dec 2023Plain language summary Pyrazolo[3,4-]pyrimidines are chemical compounds possessing remarkable versatility and significance in both biological and chemical contexts....
Plain language summary Pyrazolo[3,4-]pyrimidines are chemical compounds possessing remarkable versatility and significance in both biological and chemical contexts. These compounds are composed of specific arrangements of atoms, forming a unique ring structure, which is able to form bonds in a similar way as purines do. In the realm of chemistry, pyrazolo[3,4-]pyrimidines showcase impressive flexibility due to their ability to easily react with various molecules, opening avenues for the creation of novel compounds with diverse properties for potential applications in medicinal chemistry. In a biological context, pyrazolo[3,4-]pyrimidines play a crucial role due to their interaction with proteins such as enzymes. In fact, these compounds can impact various biological processes, including cancer cell proliferation, oxidative stress and inflammation. This has led to investigations into their potential as therapeutic agents: by designing pyrazolo[3,4-]pyrimidines with specific biological targets in mind, new drugs can be developed for the effective treatment of a range of medical conditions. Finally, novel administration tools (e.g., nanomaterials and functionalized liposomes) are being studied as effective ways to overcome the main unwanted characteristics of pyrazolo[3,4-]pyrimidines (scarce solubility and off-target side effects), thereby increasing their efficacy and specificity toward cell targets. In conclusion, pyrazolo[3,4-]pyrimidines are fascinating molecules with a dual role in chemistry and biology. Their adaptability in chemical reactions makes them valuable building blocks for designing new compounds with diverse applications. Additionally, their interaction with biological molecules holds promise for the development of innovative medicines. Ongoing research into the properties and behaviors of these compounds could lead to significant advancements in both scientific fields.
Topics: Humans; Pyrimidines; Solubility; Neoplasms; Liposomes; Cell Proliferation; Structure-Activity Relationship
PubMed: 37933597
DOI: 10.4155/fmc-2023-0274 -
Journal of Medicinal Chemistry Apr 2024Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context... (Review)
Review
Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.
Topics: Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Allosteric Regulation; Drug Approval; Antineoplastic Agents; Pyrroles; Animals
PubMed: 38592948
DOI: 10.1021/acs.jmedchem.4c00075 -
Chemical Senses Jan 2024The savory or umami taste of the amino acid glutamate is synergistically enhanced by the addition of the purines inosine 5'-monophosphate (IMP) and guanosine...
The savory or umami taste of the amino acid glutamate is synergistically enhanced by the addition of the purines inosine 5'-monophosphate (IMP) and guanosine 5'-monophosphate (GMP) disodium salt. We hypothesized that the addition of purinergic ribonucleotides, along with the pyrimidine ribonucleotides, would decrease the absolute detection threshold of (increase sensitivity to) l-glutamic acid potassium salt (MPG). To test this, we measured both the absolute detection threshold of MPG alone and with a background level (3 mM) of 5 different 5'-ribonucleotides. The addition of the 3 purines IMP, GMP, and adenosine 5'-monophosphate (AMP) lowered the MPG threshold in all participants (P < 0.001), indicating they are positive modulators or enhancers of glutamate taste. The average detection threshold of MPG was 2.08 mM, and with the addition of IMP, the threshold was decreased by approximately 1.5 orders of magnitude to 0.046 mM. In contrast to the purines, the pyrimidines uridine 5'-monophosphate (UMP) and cytidine 5'-monophosphate (CMP) yielded different results. CMP reliably raised glutamate thresholds in 10 of 17 subjects, suggesting it is a negative modulator or diminisher of glutamate taste for them. The rank order of effects on increasing sensitivity to glutamate was IMP > GMP> AMP >> UMP// CMP. These data confirm that ribonucleotides are modulators of glutamate taste, with purines enhancing sensitivity and pyrimidines displaying variable and even negative modulatory effects. Our ability to detect the co-occurrence of glutamate and purines is meaningful as both are relatively high in evolutionarily important sources of nutrition, such as insects and fermented foods.
Topics: Humans; Glutamic Acid; Ribonucleotides; Taste; Guanosine Monophosphate; Uridine Monophosphate; Purines; Inosine Monophosphate; Sodium Glutamate
PubMed: 38197318
DOI: 10.1093/chemse/bjad049 -
Blood Jun 2024We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-doxorubicin... (Randomized Controlled Trial)
Randomized Controlled Trial
We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-doxorubicin [Adriamycin]-dexamethasone) cycle 1 when combined with imatinib in adults with Philadelphia-positive acute lymphoblastic leukemia. In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 of 265 planed patients, the data and safety monitoring board decided to hold the randomization because of an excess of relapse in the investigational arm. Among the 155 evaluable patients, 76 received Ara-C during consolidation (arm A) and 79 did not (arm B). Overall, 133 patients (85%) underwent SCT, 93 allogeneic and 40 autologous. The noninferiority end point regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B compared with arm A (31.3% [95% confidence interval {CI}, 21.1%-41.9%] vs 13.2% [95% CI, 6.7%-21.9%]; P = .017), which translated to a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival was 79.0% (95% CI, 70.6%-89.3%) in arm A vs 73.4% (95% CI, 63.9%-84.4%) in arm B (P = .35). Despite a noninferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492.
Topics: Humans; Cytarabine; Female; Male; Adult; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Pyrimidines; Aged; Young Adult; Adolescent; Fusion Proteins, bcr-abl; Hematopoietic Stem Cell Transplantation
PubMed: 38452207
DOI: 10.1182/blood.2023023502 -
European Journal of Medicinal Chemistry Dec 2023Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity....
Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC 0.087and 0.105 μM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC 0.82 and 4.13 μM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC 3.36, 1.40 and 3.49 μM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes.
Topics: Humans; Molecular Structure; Structure-Activity Relationship; Cell Line, Tumor; Antineoplastic Agents; Cell Proliferation; Pyrimidines; Molecular Docking Simulation; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases
PubMed: 37922829
DOI: 10.1016/j.ejmech.2023.115918 -
Immune modulation in chronic myeloid leukaemia patients treated with nilotinib and interferon-alpha.British Journal of Haematology Sep 2023The addition of interferon to tyrosine kinase inhibitors (TKIs), to improve deep molecular response (DMR) and potentially treatment-free remission (TFR) rates in...
The addition of interferon to tyrosine kinase inhibitors (TKIs), to improve deep molecular response (DMR) and potentially treatment-free remission (TFR) rates in chronic-phase chronic myeloid leukaemia (CP-CML) patients is under active investigation. However, the immunobiology of this combination is poorly understood. We performed a comprehensive longitudinal assessment of immunological changes in CML patients treated with nilotinib and interferon-alpha (IFN-α) within the ALLG CML11 trial (n = 12) or nilotinib alone (n = 17). We demonstrate that nilotinib+IFN transiently reduced absolute counts of natural killer (NK) cells, compared with nilotinib alone. Furthermore, CD16 -cytolytic and CD57 CD62L -mature NK cells were transiently reduced during IFN therapy, without affecting NK-cell function. IFN transiently increased cytotoxic T-lymphocyte (CTL) responses to leukaemia-associated antigens (LAAs) proteinase-3, BMI-1 and PRAME; and had no effect on regulatory T cells, or myeloid-derived suppressor cells. Patients on nilotinib+IFN who achieved MR4.5 by 12 months had a significantly higher proportion of NK cells expressing NKp46, NKp30 and NKG2D compared with patients not achieving this milestone. This difference was not observed in the nilotinib-alone group. The addition of IFN to nilotinib drives an increase in NK-activating receptors, CTLs responding to LAAs and results in transient immune modulation, which may influence earlier DMR, and its effect on long-term outcomes warrants further investigation.
Topics: Humans; Dasatinib; Interferon-alpha; Protein Kinase Inhibitors; Pyrimidines; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Antigens, Neoplasm
PubMed: 37482935
DOI: 10.1111/bjh.18984 -
Journal of Medicinal Chemistry Nov 2023The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based...
The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based on the structural analysis of MRTX1133 in complex with KRAS, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (, , and ) that showed higher potency in suppressing the clonogenic growth of KRAS-dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRAS with IC values between 0.48 and 1.21 nM. These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high and potency of these new inhibitors call for further profiling.
Topics: Animals; Humans; Mice; Mutation; Proto-Oncogene Proteins p21(ras); Pyrimidines
PubMed: 37921024
DOI: 10.1021/acs.jmedchem.3c01724 -
Bioorganic Chemistry Nov 2023Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor...
Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging. Herein, we reported a novel series of 1H-pyrazolo[3,4-d]pyrimidine derivatives as HPK1 inhibitors by structure-based rational design. The optimal compound 10n significantly inhibited HPK1 with an IC value of 29.0 nM and the phosphorylation of SLP76 at a concentration as low as 0.1 μM. Furthermore, compound 10n exhibited good selectivity over a panel of 25 kinases, including GLK from the same MAP4K family. Together, the current study provided a novel, potent, and selective HPK1 inhibitor, acting as a lead compound for the future development of cancer immunotherapy.
Topics: Protein Serine-Threonine Kinases; Phosphorylation; Antihypertensive Agents; Pyrimidines
PubMed: 37659145
DOI: 10.1016/j.bioorg.2023.106811 -
JCI Insight Apr 2024Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been...
Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.
Topics: Leukemia, Myeloid, Acute; Humans; Pyrimidines; Mice; Animals; Dihydroorotate Dehydrogenase; Immunotherapy; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female
PubMed: 38646934
DOI: 10.1172/jci.insight.173646