PI3Kα inhibitors(Phosphatidylinositol 3 kinase alpha inhibitors), PI3Kβ inhibitors(Phosphatidylinositol 3 kinase beta inhibitors), PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

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Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid Leukemia

Inactive Indication-

Originator Organization

Fudan University

Active Organization

Fudan University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC22H14ClFN6O2S

InChIKeyRVHGXIUOUJYWPJ-UHFFFAOYSA-N

CAS Registry2641899-38-7

100 Clinical Results associated with FD-274

100 Translational Medicine associated with FD-274

100 Patents (Medical) associated with FD-274

Literatures (Medical) associated with FD-274

01 Dec 2023·Cardiovascular toxicology

Systematical Evaluation of the Structure-Cardiotoxicity Relationship of 7-Azaindazole-based PI3K Inhibitors Designed by Bioisosteric Approach.

Article

Author: Wu, Tianze ; Pi, Yan ; Xu, Jun ; Ling, Yun ; Guo, Jianhua ; Yang, Chengbin ; Lu, Mingzhu ; Cai, Tong ; Lu, Lei ; Geng, Fang ; Zhou, Yaming ; Chen, Yi

A growing concern of cardiotoxicity induced by PI3K inhibitors has raised the requirements to evaluate the structure-cardiotoxicity relationship (SCR) in the development process of novel inhibitors. Based on three bioisosteric 7-azaindazole-based candidate inhibitors namely FD269, FD268 and FD274 that give same order of inhibitory concentration 50% (IC₅₀) magnitude against PI3Ks, in this work, we proposed to systematically evaluate the SCR of 7-azaindazole-based PI3K inhibitors designed by bioisosteric approach. The 24-h lethal concentrations 50% (LC₅₀) of FD269, FD268 and FD274 against zebrafish embryos were 0.35, 4.82 and above 50 μM (not detected), respectively. Determination of the heart rate, pericardial and yolk-sac areas and vascular malformation confirmed the remarkable reduction in the cardiotoxicity of from FD269 to FD268 and to FD274. The IC₅₀s of all three compounds against the hERG channel were tested on the CHO cell line that constitutively expressing hERG channel, which were all higher than 20 μM. The transcriptomic analysis revealed that FD269 and FD268 induced the up-regulation of noxo1b, which encodes a subunit of an NADPH oxidase evoking the oxidative stress. Furthermore, immunohistochemistry tests confirmed the structure-dependent attenuation of the overproduction of ROS and cardiac apoptosis. Our results verified the feasibility of bioisosteric replacement to attenuate the cardiotoxicity of 7-azaindazole-based PI3K inhibitors, suggesting that the screening for PI3K inhibitors with both high potency and low cardiotoxicity from bioisosteres would be a beneficial trial.

01 Oct 2023·European Journal of Medicinal Chemistry

Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia

Article

Author: Ling, Yun ; Zhou, Yaming ; Wu, Tianze ; Gao, Yunjian ; Jia, Yu ; Deng, Mingli ; Wang, Jianxin ; Yang, Yongtai ; Liu, Xiaofeng ; Chen, Yi ; Yang, Chengbin

PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC₅₀ values against PI3Kα/β/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC₅₀ values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

100 Deals associated with FD-274

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	-	Fudan University	-

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