Bcr-Abl modulators(Bcr-Abl tyrosine kinase modulators), ERK1 inhibitors(Extracellular-signal-regulated kinase1 inhibitors), FLT3 modulators(Tyrosine-protein kinase receptor FLT3 modulators)

+ [1]

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Adult Acute Myeloblastic Leukemia

Inactive Indication-

Originator Organization

Cincinnati Children's Hospital Medical Center

Active Organization

Cincinnati Children's Hospital Medical Center

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with Pluripotin

100 Translational Medicine associated with Pluripotin

100 Patents (Medical) associated with Pluripotin

Literatures (Medical) associated with Pluripotin

25 Apr 2023·Blood Advances

Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML

Article

Author: Ansari, Sekhu ; Azam, Mohammad ; Azhar, Mohammad ; Menke, Jacob ; Kincaid, Zachary ; Ahmed, Arhama ; Wunderlich, Mark ; Seibel, William ; Khan, Areeba ; Schwieterman, Joshua ; Shehzad, Rammsha ; Amir, Noor ; Reaves, Angela ; Latif, Tahir ; Kesarwani, Meenu ; Syed, Nuha

AbstractDespite significant advancements in developing selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance to treatment is common even on continued therapy. Acquisition of on-target mutations or adaptation to MAPK, JAK2, and ABL signaling pathways drive treatment failure and disease relapse. Although combinatorial targeting of all escape routes in preclinical models demonstrated its efficacy, the clinical application is challenging owing to drug-drug interaction and differing pharmacokinetics of the inhibitors. We reasoned that selective polypharmacological targeting could lead to a durable response with reduced toxicity. A cell-based screening was carried out to identify inhibitors targeting FLT3, RAS-MAPK, BCR-ABL, and JAK2 to target the adaptive resistance observed with FLT3 inhibitors. Here, we show that pluripotin is an equipotent inhibitor of FLT3, BCR-ABL, and JAK2 in addition to inhibiting Ras-GAP and extracellular signal-regulated kinase 1 (ERK1). Structural modeling studies revealed that pluripotin is a type II kinase inhibitor that selectively binds with inactive conformations of FLT3, ABL, and JAK2. Pluripotin showed potent inhibitory activity on both mouse and human cells expressing FLT3ITD, including clinically challenging resistant mutations of the gatekeeper residue, F691L. Likewise, pluripotin suppressed the adaptive resistance conferred by the activation of RAS-MAPK pathways, BCR-ABL, and JAK2 signaling. Treatment with pluripotin curbed the progression of acute myeloid leukemia (AML) in multiple in vivo models including patient-derived primary AML cells in mouse xenotransplants. As a proof of concept, we demonstrate that targeted polypharmacological inhibition of key signaling nodes driving adaptive resistance can provide a durable response.

01 Feb 2023·Journal of International Medical Research

Inhibition of DNA methylation attenuates lung ischemia–reperfusion injury after lung transplantation

Article

Author: Liu, Ming-yuan ; Xu, Guang-xiao ; Tai, Qi-hang ; Sun, Xi-kun ; Ju, Ying-nan ; Gao, Wei ; Tan, Jing ; Liu, Heng-yu ; Qiu, Lin ; Jia, Bao-wei

Objective DNA methylation plays an important role in inflammation and oxidative stress. This study aimed to investigate the effect of inhibiting DNA methylation on lung ischemia–reperfusion injury (LIRI). Methods We adopted a completely random design for our study. Thirty-two rats were randomized into the sham, LIRI, azathioprine (AZA), and pluripotin (SC1) groups. The rats in the LIRI, AZA, and SC1 groups received left lung transplantation and intravenous injection of saline, AZA, and SC1, respectively. After 24 hours of reperfusion, histological injury, the arterial oxygen partial pressure to fractional inspired oxygen ratio, the wet/dry weight ratio, protein and cytokine concentrations in lung tissue, and DNA methylation in lung tissue were evaluated. The pulmonary endothelium that underwent hypoxemia and reoxygenation was treated with AZA or SC1. Endothelial apoptosis, chemokines, reactive oxygen species, nuclear factor-κB, and apoptotic proteins in the endothelium were studied. Results Inhibition of DNA methylation by AZA attenuated lung injury, inflammation, and the oxidative stress response, but SC1 aggravated LIRI injury. AZA significantly improved endothelial function, suppressed apoptosis and necrosis, reduced chemokines, and inhibited nuclear factor-κB. Conclusions Inhibition of DNA methylation ameliorates LIRI and apoptosis and improves pulmonary function via the regulation of inflammation and oxidative stress.

01 Apr 2018·CytotechnologyQ4 · BIOLOGY

Comparison of culture media indicates a role for autologous serum in enhancing phenotypic preservation of rabbit limbal stem cells in explant culture

Q4 · BIOLOGY

Article

Author: Durak, İsmet ; Baysal, Kemal ; Gürdal, Mehmet ; Barut Selver, Özlem

In this study, we aimed to compare the effects of six different cell culture media and autologous serum (AS) on the phenotypic characteristics of rabbit limbal epithelial stem cells (LESC) cultivated on porous polyethylene terephthalate (PET) membranes. Limbal explants from rabbit corneas were grown on PET membrane inserts in five different media: DMEM-F12 with fetal bovine serum (FBS) (DMEM-F12-FBS), with pluripotin (DMEM-F12-pluripotin) and with autologous serum (DMEM-F12-AS), Epilife, Keratinocyte Serum Free Medium (KSFM) and Defined-Keratinocyte Serum Free Medium. The effects of different media were evaluated by total cell yield from explants, measuring the expression of proteins by immunofluorescence and gene expression by Real Time PCR. In all five media tested, most of the limbal epithelial cells (LEC) which proliferated from explants were positive for cytokeratin (CK) 14 (85-90%), indicating that all five media support the growth of LESC from explants. The expression of differentiation markers; CK 3 and 12 was highest in DMEM-F12-FBS (56%), was lower in Epilife and KSFM (26 and 19%, respectively), with the lowest values (13%) obtained in DMEM-F12-AS. Gene expression of limbal cultures on PET membrane inserts was compared to fresh limbal tissue. In DMEM-F12-FBS, DMEM-F12-pluripotin, and DMEM-F12-AS, expression of potential LESC markers CXCR4 and polycomb complex protein BMI-1 were similar to limbal tissue. DMEM-F12 with 10% AS maintained a higher percentage of potential stem cell marker genes and lower expression of genes involved in differentiation compared to Epilife or KSFM. Our study shows that rabbit LEC can be cultivated on PET inserts using DMEM-F12 with autologous serum without a requirement for amniotic membrane or feeder cells.

100 Deals associated with Pluripotin

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Adult Acute Myeloblastic Leukemia	Preclinical	US	Cincinnati Children's Hospital Medical Center	09 Dec 2022

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