PI3Kδ x Vps34

Last update 08 May 2025

Basic Info

Related Targets

PI3KδVps34

Drugs associated with PI3Kδ x Vps34

PI3KD/V-IN-01

Target

PI3Kδ x Vps34

Mechanism

PI3Kδ inhibitors [+1]

Active Org.-

Originator Org.

University of Science & Technology of China

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PI3Kδ x Vps34

100 Translational Medicine associated with PI3Kδ x Vps34

0 Patents (Medical) associated with PI3Kδ x Vps34

Literatures (Medical) associated with PI3Kδ x Vps34

23 Jan 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target

Q1 · MEDICINE

Article

Author: Hamblin, J. Nicole ; Reinhard, Friedrich B. M. ; Grandi, Paola ; Livia, Stefano ; Down, Kenneth ; Bertrand, Sophie M. ; Hessel, Edith M. ; Mallett, David ; Maxwell, Aoife ; Edwards, Chris D. ; Thomas, Daniel A. ; Barton, Nick ; Taylor, Jonathan A. ; Rau, Christina ; Dumpelfeld, Birgit ; Rowedder, James ; Bantscheff, Marcus ; Rowland, Paul ; Gore, Paul M. ; Amour, Augustin ; Henley, Zoe A. ; Keeling, Steve ; Convery, Maire ; Bergamini, Giovanna ; Price, Mark

Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.

16 Aug 2016·Oncotarget

Simultaneous inhibition of Vps34 kinase would enhance PI3Kδ inhibitor cytotoxicity in the B-cell malignancies

Article

Author: Wang, Aoli ; Liu, Juanjuan ; Griffin, James. D. ; Chen, Cheng ; Liu, Jing ; Xu, Yunhe ; Zhao, Zheng ; Stone, Richard M. ; Qi, Ziping ; Deng, Yuanxin ; Brown, Jennifer R. ; Zhang, Xin ; Liang, Xiaofei ; Weisberg, Ellen L. ; Fernandes, Stacey M. ; Liu, Feiyang ; Wang, Wenchao ; Liu, Xiaochuan ; Galinsky, Ilene A. ; Loh, Teckpeng ; Wu, Hong ; Zou, Fengming ; Liu, Qingsong ; Zhang, Shanchun ; Wang, Beilei ; Wang, Li

PI3Kδ has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kδ inhibitor, CAL-101, inhibition of PI3Kδ itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3Kδ inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3Kδ and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3Kδ-targeted inhibitors. We discovered a highly potent ATP-competitive PI3Kδ/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3Kδ and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3Kδ and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3Kδ and Vps34 might be a useful approach to improve the PI3Kδ inhibitor's anti-tumor efficacy.

01 May 2003·Archives of Gerontology and GeriatricsQ3 · MEDICINE

A positive role of phosphatidylinositol 3-kinase in aging phenotype expression in cultured human diploid fibroblasts

Q3 · MEDICINE

Article

Author: Kuang Yu Chen ; Koozi Matuoka ; Tadaomi Takenawa

In order to detect the role that phosphatidylinositol 3-kinase (PI3K) plays in the aging of human diploid fibroblasts, we analyzed cellular inositol phospholipids and expression of PI3Ks. In aged cells a decrease in phosphatidylinositol 3,4-bisphosphate (PI3,4P(2)) was notable, while phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 4,5-bisphosphate (PI4,5P(2)) decreased slightly. On the other hand, the messages of PI3K IIalpha, Vps34, and p110delta decreased and that of PI3K IIbeta increased during aging. These changes might relate to the aging phenomena, with the PI3K subspecies functioning differentially. Consistently, a PI3K inhibitor LY294002 greatly suppressed enlargement and flattening of cell body and nucleus as well as cell proliferation, both phenotypes being typical of aged cells. An oxidative stress, pulse exposure to hydrogen peroxide (H(2)O(2)), induced these senescent cell-like phenotypes, which LY294002 was also able to abolish. Upon examining three different cell systems (HL-60, N1E-115, and PC-12 cells) we found clear parallelism in a cellular event between the dependence on a PI3K activity and the sensitivity to H(2)O(2). On the analogy of these relationships, we could hypothesize that expression of an aging phenotype such as the morphogenesis is positively promoted by some PI3K subspecies, if such a phenotype as cell cycling is negatively affected by attenuation of another PI3K function in the course of cellular aging.

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