Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

Al-Sha’er, Mahmoud A.; Taha, Mutasem O.; Alelaimat, Mahmoud A.

doi:10.1007/s00044-023-03057-3

Cited by 6 publications

(2 citation statements)

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“…The % inhibition of compounds of the synthetic compounds on the normal cell line is variable with potential inhibition of compounds OMS5 and OMS14, which indicates the toxicity of the highest active compounds on the normal cell line, although the effect is higher on the cancerous cell line, which indicates a margin of safety of OMS5 and OMS14. However, for further development of synthetic compounds in the future to enhance the safety and reduce the toxicity on normal cell lines, it is suggested to prepare halogenated derivatives that may have a positive effect on kinase enzymes. , Moreover, to mitigate the toxicity on normal cells, the next steps will involve developing nanocarriers of the most active compounds specifically designed to target cancer cells instead of normal cells. , …”

Section: Resultsmentioning

confidence: 99%

“…However, for further development of synthetic compounds in the future to enhance the safety and reduce the toxicity on normal cell lines, it is suggested to prepare halogenated derivatives that may have a positive effect on kinase enzymes. 66 , 67 Moreover, to mitigate the toxicity on normal cells, the next steps will involve developing nanocarriers of the most active compounds specifically designed to target cancer cells instead of normal cells. 68 , 69 …”

Section: Resultsmentioning

confidence: 99%

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Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents

Salih,

Al-Sha’er,

Basheer

2024

ACS Omega

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Sixteen novel 2-aminobenzothiazole compounds with different amines or substituted piperazine moieties were designed, synthesized, and tested using various methods. Potential interactions were assessed by docking new compounds in the adenosine triphosphate (ATP) binding domain of the PI3Kγ enzyme (PDB code: 7JWE) by nucleophilic substitution or solvent-free/neat fusion for docked compound synthesis. Final 2-aminobenzothiazole compounds were characterized by direct probe gas chromatography-mass spectrometry (GC-MS), proton ( 1 H-NMR), carbon-13 ( 13 C-NMR), and attenuated total reflectance-infrared Fourier transform infrared (ATR FT-IR). The synthesized compounds were investigated for anticancer activities on lung cancer (A549) and breast cancer (MCF-7) cell lines. The compounds' PI3Kγ inhibition was evaluated at a 100 μM concentration. 4-Nitroaniline and piperazine-4-nitroaniline combination in OMS5 and OMS14 reduced lung and breast cancer cell line growth. IC 50 values for OMS5 and OMS14, the strongest compounds, ranged from 22.13 to 61.03 μM. OMS1 and OMS2 inhibited PI3Kγ at the highest rates (47 and 48%, respectively) at a 100 μM concentration. Results show that the PI3Kγ enzyme suppression is not the main mechanism behind these OMS5 and OMS14 anticancer effects. CDK2, Akt, mTOR, and p42/44 MAPK are affected. EGF receptor suppression matters. AKT1, AKT3, CDK1/cyclin B, PDK1 direct, PIK3CA E542 K/ PIK3R1 (p110 α/p85 α), PIK3CD/PIK3R1 (p110 δ/p85 α), and PKN inhibition were measured to evaluate the possible mechanism of compound OMS14. PIK3CD/PIK3R1 (p110 δ/p85 α) is the most, with 65% inhibition, suggesting a possible mechanism of anticancer properties. Furthermore, the NCI 60-cell line inhibition demonstrates promising broad anticancer inhibition against numerous cancer cell lines of OMS5 and OMS14, which could be good lead compounds for future development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents

Salih,

Al-Sha’er,

Basheer

2024

ACS Omega

Self Cite

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Discovery of novel indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitors: pharmacophore-based 3D-QSAR, Gaussian field-based 3D-QSAR, docking, and binding free energy studies

et al. 2023

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The Current State of Systemic Therapy of Metastatic Uveal Melanoma

Koch,

Heppt,

Berking

2024

Am J Clin Dermatol

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Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.

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Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

Cited by 6 publications

References 58 publications

Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents

Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents

Discovery of novel indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitors: pharmacophore-based 3D-QSAR, Gaussian field-based 3D-QSAR, docking, and binding free energy studies

The Current State of Systemic Therapy of Metastatic Uveal Melanoma

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