PI3Kδ x PI3Kβ x mTOR x PI3Kα

Last update 23 Jan 2025

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 Jan 2025·Bioorganic Chemistry

Current developments in PI3K-based anticancer agents: Designing strategies, biological activity, selectivity, structure-activity correlation, and docking insight

Review

Author: B V, Manjushree ; Mounika, S ; Pal, Rohit ; D, Anjan ; Matada, Gurubasavaraja Swamy Purawarga ; M P, Viji ; E, Haripriya ; K, Hemalatha ; Ashadul Sk, Md

The phospatidylinositol-3 kinase (PI3K) pathway is a critical intracellular signalling mechanism that is changed or amplified in a variety of cancers, including breast, gastric, ovarian, colorectal, prostate, glioma, and endometrial. PI3K signalling is important for cancer cell survival, angiogenesis, and metastasis, making it a promising therapeutic target. The PI3K kinases in their different isoforms, namely α, β, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for the therapeutic failure of current therapeutics. There are several current and completed clinical trials using PI3K inhibitors (pan, isoform-specific, and dual PI3K/mTOR) to develop effective PI3K inhibitors capable of overcoming resistance to existing drugs. However, the bulk of these inhibitors have had their indications revoked or voluntarily withdrawn due to concerns about their harmful consequences. Several inhibitors containing medicinally privileged scaffolds like thiazole, triazine, benzimidazole, podophyllotoxin, pyridine, quinazoline, thieno-triazole, pyrimidine, triazole, benzofuran, imidazo-pyridazine, oxazole, coumarin, and azepine derivatives have been explored to target the PI3K pathway and/or a specific isoform in the current overview. This article reviews the structure, biological activities, and clinical status of PI3K inhibitors. It focuses on the development techniques, docking insight, and structure-activity connections of PI3K-based inhibitors. The findings provide useful insights and future approaches for the development of promising PI3K-based inhibitors.

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.

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