Last update 01 Nov 2024

PI3Kδ x PI3Kβ x mTOR x PI3Kα

Last update 01 Nov 2024

Basic Info

Related Targets

PI3KδPI3KβmTOR[+1]

Drugs associated with PI3Kδ x PI3Kβ x mTOR x PI3Kα

FD-274

Target

PI3Kα x PI3Kβ x PI3Kδ x mTOR

Mechanism

PI3Kα inhibitors [+3]

Active Org.

Fudan University

Originator Org.

Fudan University

Active Indication

Acute Myeloid Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PI3Kδ x PI3Kβ x mTOR x PI3Kα

100 Translational Medicine associated with PI3Kδ x PI3Kβ x mTOR x PI3Kα

0 Patents (Medical) associated with PI3Kδ x PI3Kβ x mTOR x PI3Kα

Literatures (Medical) associated with PI3Kδ x PI3Kβ x mTOR x PI3Kα

01 Dec 2023·International Journal of Toxicology

Non-Clinical Toxicology Evaluation of the Novel Non-ATP Competitive Oral PI3 Kinase Delta Inhibitor Roginolisib

Article

Author: Schmitt, Michael ; van der Veen, Lars ; Lahn, Michael ; Deken, Marcel A.

Roginolisib (IOA-244) is a novel, non-ATP competitive phosphoinositide-3-kinase (PI3K) delta inhibitor that regulates Akt/mTOR signaling. Roginolisib was administered once daily to rats and dogs in dose-range finding (DRF) and 4-week GLP toxicology studies. Free plasma levels of roginolisib exceeded the cellular target engagement IC90 for PI3Kδ for ≥12 hours at doses of 5 mg/kg, the IC90 for PI3Kβ for ≥2 hours at doses ≥15 mg/kg, and the IC50 for PI3Kα for ≥2 hours at dose levels ≥45 mg/kg. Toxicity in rats occurred at doses ≥100 mg/kg. In dogs, we observed dose-dependent skin and gastrointestinal toxicity and doses ≥30 mg/kg had a greater incidence of mortality. Lymphoid tissue toxicity occurred in both species. Toxicities in dogs observed at the ≥15 mg/kg dose, affecting the digestive mucosa, liver, and skin, cleared after treatment cessation. Doses ≤75 mg/kg were tolerated in rats and the no-observed-adverse-effect-level (NOAEL) in rats was 15 mg/kg. Due to mainly epithelial lesions of the skin at 5 mg/kg and necrotizing damage of the intestinal epithelia at ≥15 mg/kg, no NOAEL was determined in dogs. However, the adverse effects observed in dogs at 5 mg/kg were considered monitorable and reversible in patients with advanced malignancies. Furthermore, the PK profile subsequently proved to be a decisive factor for achieving selective PI3Kδ inhibition without the toxicities observed in dogs. As the result of the unique PK profile of roginolisib, patients were able to take daily roginolisib without dose modification and showed pharmacodynamic PI3Kδ inhibition over several months without gastrointestinal or dermatologic toxicities.

01 Jun 2023·Journal of Molecular Graphics and Modelling

Binding and selectivity studies of phosphatidylinositol 3-kinase (PI3K) inhibitors

Article

Author: Yang, Stephen X ; Sabirianov, Matthew ; Zhong, Haizhen A ; Goettsch, Kaitlin ; Al Hasan, Mohammad ; Redwine, Grace

Overexpression of the Phosphatidylinositol 3-kinase (PI3K) proteins have been observed in cancer cells. Targeting the phosphatidylinositol 3-kinase (PI3K) signaling transduction pathway by inhibition of the PI3K substrate recognition sites has been proved to be an effective approach to block cancer progression. Many PI3K inhibitors have been developed. Seven drugs have been approved by the US FDA with a mechanism of targeting the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In this study, we used docking tools to investigate selective binding of ligands toward four different subtypes of PI3Ks (PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ). The affinity predicted from both the Glide dock and the Movable-Type (MT)-based free energy calculations agreed well with the experimental data. The validation of our predicted methods with a large dataset of 147 ligands showed very small mean errors. We identified residues that may dictate the subtype-specific binding. Particularly, residues Asp964, Ser806, Lys890 and Thr886 of PI3Kγ might be utilized for PI3Kγ-selective inhibitor design. Residues Val828, Trp760, Glu826 and Tyr813 may be important for PI3Kδ-selective inhibitor binding.

01 Mar 2021·European Journal of Medicinal ChemistryQ1 · MEDICINE

Structural optimization towards promising β-methyl-4-acrylamido quinoline derivatives as PI3K/mTOR dual inhibitors for anti-cancer therapy: The in vitro and in vivo biological evaluation

Q1 · MEDICINE

Article

Author: He, Ruoyu ; Ping, Li ; Lv, Xiaoqing ; Xu, Bingyong

Built upon the 4-acrylamido quinoline derivative 4, a previously discovered PI3K/mTOR dual inhibitor, structural modification was undertaken in this study with the attempt to improve its oral exposure via introducing steric hindrance to the 4-acrylamido functionality. Consequently, 14d, as the representative among the synthesized compounds, exhibited IC₅₀ values of 0.80, 0.67, 1.30, 1.30 and 5.0 nM against PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and mTOR, respectively. Besides, 14d displayed comparable anti-proliferative activity against both PC3 and U87MG cell lines to that of the positive reference GSK2126458 with respective GI₅₀ value of 0.36 and 0.14 μM. Kinase selectivity assay showed that 14d was selective to PI3K family. In U87MG cells, 14d can strongly down-regulate PI3K/Akt/mTOR pathway via blocking both PI3K and mTOR signaling at the concentration as low as 25 nM. Importantly, following a PO dose of 5 mg/kg in male SD rats, 14d displayed favorable oral exposure (AUC_0-t = 1336.16 h × ng/mL, AUC_0-∞ = 1447.63 h × ng/mL) and high maximum plasma concentration (C_max = 903.00 ng/mL). In a U87MG glioblastoma xenograft model, tumor growth inhibition of 93.5% and tumor regression were observed at PO dose of 30 and 60 mg/kg, respectively. Meanwhile, no overt loss of body weight was observed in the 14d-treated groups. Taken together, 14d, by virtue of its attractive performance, merits further development as a potential anti-tumor candidate.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis