Identification of PI3K/HDAC Dual-targeted inhibitors with subtype selectivity as potential therapeutic agents against solid Tumors: Building HDAC6 potency in a Quinazolinone-based PI3Kδ-selective template

Li, Zhi; Zhao, Chenglin; He, Ge; Wang, Yujie; Wang, Yan; Ma, Xiaodong

doi:10.1016/j.bmc.2022.117028

Cited by 7 publications

(6 citation statements)

References 37 publications

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“…The second combination investigated was between gedatolisib and tubastatin A, for which we observed additive effects in combinations using lower concentrations of the compounds, while there was a prevalence of the synergistic effect as the concentrations increased ( Table 5 ). Our results agree with literature data [ 22 , 23 ], which describe that the combination of PI3K and HDAC-6 inhibitors has synergistic effects, resulting in an increase in the cytotoxic activity of the combination when compared with the cytotoxic effect of the species alone, as we have found for gedatolisib and tubastatin A ( Table 4 ).…”

Section: Resultssupporting

confidence: 93%

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

Pillpe-Meza,

Gouveia,

Barbosa

et al. 2024

Pharmaceuticals

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Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC50 = 23 µM), human leukaemia cell line CCRF-CEM (IC50 = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by parallel artificial membrane permeability—gastrointestinal tract (PAMPA—GIT) and low permeation by parallel artificial membrane permeability—blood–brain barrier (BBB) (PAMPA—BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.

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Section: Resultssupporting

confidence: 93%

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

Pillpe-Meza,

Gouveia,

Barbosa

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…The second combination investigated was between gedatolisib and tubastatin A, for which we observed additive effects in combinations using lower concentrations of the compounds, while there was a prevalence of the synergistic effect as the concentrations increased (Table 5). Our results agree with literature data [22,23], which describe that the combination of PI3K and HDAC-6 inhibitors has synergistic effects, resulting in an increase in the cytotoxic activity of the combination when compared with the cytotoxic effect of the species alone, as we have found for gedatolisib and tubastatin A (Table 4). LASSBio-2208, previously described as an inhibitor of PI3Kα (IC 50 = 46.3 nM), PI3Kβ (IC 50 = 72.8 nM), PI3Kδ (IC 50 = 72.4 nM) and HDAC-6 (IC 50 = 15.3 nM) (Figure 1), displayed both synergistic and additive effects, when combined with gedatolisib and tubastatin A.…”

Section: Synergism Study By Mtt On Ccrf-cem Cell Linesupporting

confidence: 93%

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its DMPK Profile

Pillpe-Meza,

Gouveia,

Barbosa

et al. 2024

Preprint

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Inappropriate expression of histone deacetylase (HDAC6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway are common aberrations observed in cancers. LASSBio-2208, was previously described as a dual inhibitor in the nanomolar range of HDAC6 and PI3Kα, being three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its DMPK in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on MCF-7 (IC50 = 23 µM), CCRF-CEM (IC50 = 8.54 µM) and MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on hPBMC. In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by PAMPA-GIT and low permeation through the blood-brain barrier by PAMPA-BBB, exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentration corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.

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“…Besides single-targeted HDAC inhibitors, Liou and colleagues reported in 2020 that two dual HSP90/HDAC inhibitors Liou-20 and Liou-26 decreased the expression levels of PD-L1 in IFNγ-treated H1975 cells . Ma and colleagues demonstrated in 2022 that Ma-59 as a dual phosphatidylinositol 3-kinase δ (PI3Kδ)/HDCA6 inhibitor downregulated the expression levels of PD-L1 in T47D cells …”

Section: Downregulators That Do Not Bind To Pd-l1mentioning

confidence: 99%

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Wang,

Yuan,

Liao

et al. 2024

J. Med. Chem.

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Targeting the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has evolved into one of the most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved for treating a variety of tumors, while the development of small-molecule PD-1/PD-L1 inhibitors has lagged far behind, with only a few small-molecule inhibitors entering clinical trials. In addition to antibody drugs and small-molecule inhibitors, reducing the expression levels of PD-L1 has attracted extensive research interest as another promising strategy to target the PD-1/PD-L1 pathway. Herein, we analyze the structures and mechanisms of molecules that reduce PD-L1 expression and classify them as degraders and downregulators according to whether they directly bind to PD-L1. Moreover, we discuss the potential prospects for developing PD-L1-targeting drugs based on these molecules. It is hoped that this perspective will provide profound insights into the discovery of potent antitumor immunity drugs. ■ SIGNIFICANCEReducing PD-L1 expression has been considered as a promising strategy to modulate the PD-1/PD-L1 pathway, which has attracted continuous research interests. This perspective focuses on analyzing the molecules capable of reducing PD-L1 expression and classifies them as degraders and down-regulators according to whether they directly bind to PD-L1. Additionally, it provides deep insights into the rational design strategies and challenges for the development of PD-L1 degraders as well as PD-L1-based combination therapies and multitarget drugs.

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Identification of PI3K/HDAC Dual-targeted inhibitors with subtype selectivity as potential therapeutic agents against solid Tumors: Building HDAC6 potency in a Quinazolinone-based PI3Kδ-selective template

Cited by 7 publications

References 37 publications

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its DMPK Profile

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

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