Aurora B inhibitors(Serine/threonine-protein kinase Aurora-B inhibitors), FLT3 inhibitors(Tyrosine-protein kinase receptor FLT3 inhibitors), PKC inhibitors(Protein kinase C inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid Leukemia with FLT3/ITD Mutation

Inactive Indication

Inflammation

Originator Organization

Gödecke GmbH

Active Organization

University of Fukui

Inactive Organization

Parke-Davis & Co. Ltd.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H18N4O

InChIKeyVWVYILCFSYNJHF-UHFFFAOYSA-N

CAS Registry136194-77-9

100 Clinical Results associated with GO-6976

100 Translational Medicine associated with GO-6976

100 Patents (Medical) associated with GO-6976

545

Literatures (Medical) associated with GO-6976

01 Sep 2024·Bone

Prkd1 regulates the formation and repair of plasma membrane disruptions (PMD) in osteocytes

Article

Author: Alhamad, Dima W ; Horne, J Luke ; Johnson, Maribeth ; Yu, Kanglun ; Tuladhar, Anik ; Shaver, Joseph C ; McGee, Wesley A ; Hamrick, Mark W ; Zhong, Roger ; Bollag, Wendy ; Cooley, Marion A ; Dorn, Jennifer ; McGee-Lawrence, Meghan E ; Hagan, Mackenzie L

We and others have seen that osteocytes sense high-impact osteogenic mechanical loading via transient plasma membrane disruptions (PMDs) which initiate downstream mechanotransduction. However, a PMD must be repaired for the cell to survive this wounding event. Previous work suggested that the protein Prkd1 (also known as PKCμ) may be a critical component of this PMD repair process, but the specific role of Prkd1 in osteocyte mechanobiology had not yet been tested. We treated MLO-Y4 osteocytes with Prkd1 inhibitors (Go6976, kbNB 142-70, staurosporine) and generated an osteocyte-targeted (Dmp1-Cre) Prkd1 conditional knockout (CKO) mouse. PMD repair rate was measured via laser wounding and FM1-43 dye uptake, PMD formation and post-wounding survival were assessed via fluid flow shear stress (50 dyn/cm²), and in vitro osteocyte mechanotransduction was assessed via measurement of calcium signaling. To test the role of osteocyte Prkd1 in vivo, Prkd1 CKO and their wildtype (WT) littermates were subjected to 2 weeks of unilateral axial tibial loading and loading-induced changes in cortical bone mineral density, geometry, and formation were measured. Prkd1 inhibition or genetic deletion slowed osteocyte PMD repair rate and impaired post-wounding cell survival. These effects could largely be rescued by treating osteocytes with the FDA-approved synthetic copolymer Poloxamer 188 (P188), which was previously shown to facilitate membrane resealing and improve efficiency in the repair rate of PMD in skeletal muscle myocytes. In vivo, while both WT and Prkd1 CKO mice demonstrated anabolic responses to tibial loading, the magnitude of loading-induced increases in tibial BMD, cortical thickness, and periosteal mineralizing surface were blunted in Prkd1 CKO as compared to WT mice. Prkd1 CKO mice also tended to show a smaller relative difference in the number of osteocyte PMD in loaded limbs and showed greater lacunar vacancy, suggestive of impaired post-wounding osteocyte survival. While P188 treatment rescued loading-induced increases in BMD in the Prkd1 CKO mice, it surprisingly further suppressed loading-induced increases in cortical bone thickness and cortical bone formation. Taken together, these data suggest that Prkd1 may play a pivotal role in the regulation and repair of the PMD response in osteocytes and support the idea that PMD repair processes can be pharmacologically targeted to modulate downstream responses, but suggest limited utility of PMD repair-promoting P188 in improving bone anabolic responses to loading.

01 Mar 2024·Journal of Biological Chemistry

Inhibition of protein kinase C increases Prdm14 level to promote self-renewal of embryonic stem cells through reducing Suv39h-induced H3K9 methylation

Article

Author: Cao, Jianjian ; Ye, Shou-Dong ; Huang, Ru ; Chen, Peng ; Ji, Junxiang

Inhibition of protein kinase C (PKC) efficiently promoted the self-renewal of embryonic stem cells (ESCs). However, information about the function of PKC inhibition remains lacking. Here, RNA-sequencing showed that the addition of Go6983 significantly inhibited the expression of de novo methyltransferases (Dnmt3a and Dnmt3b) and their regulator Dnmt3l, resulting in global hypomethylation of DNA in mouse ESCs. Mechanistically, PR domain-containing 14 (Prdm14), a site-specific transcriptional activator, partially contributed to Go6983-mediated repression of Dnmt3 genes. Administration of Go6983 increased Prdm14 expression mainly through the inhibition of PKCδ. High constitutive expression of Prdm14 phenocopied the ability of Go6983 to maintain` mouse ESC stemness in the absence of self-renewal-promoting cytokines. In contrast, the knockdown of Prdm14 eliminated the response to PKC inhibition and substantially impaired the Go6983-induced resistance of mouse ESCs to differentiation. Furthermore, liquid chromatography-mass spectrometry profiling and Western blotting revealed low levels of Suv39h1 and Suv39h2 in Go6983-treated mouse ESCs. Suv39h enzymes are histone methyltransferases that recognize dimethylated and trimethylated histone H3K9 specifically and usually function as transcriptional repressors. Consistently, the inhibition of Suv39h1 by RNA interference or the addition of the selective inhibitor chaetocin increased Prdm14 expression. Moreover, chromatin immunoprecipitation assay showed that Go6983 treatment led to decreased enrichment of dimethylation and trimethylation of H3K9 at the Prdm14 promoter but increased RNA polymerase Ⅱ binding affinity. Together, our results provide novel insights into the pivotal association between PKC inhibition-mediated self-renewal and epigenetic changes, which will help us better understand the regulatory network of stem cell pluripotency.

01 Jan 2024·Blood Cells, Molecules, and Diseases

The role of PKC in X-ray-induced megakaryocyte apoptosis and thrombocytopenia

Article

Author: Liu, Chunliang ; Yan, Yan ; Meng, Fanbi ; Dai, Kesheng ; Khan, Muhammad Shoaib ; Sun, Chenglin ; Hu, Renping ; Chen, Shuang ; Xia, Yue ; Wan, Jun ; Yang, Mengnan

Thrombocytopenia is a critical complication after radiation therapy and exposure. Dysfunction of megakaryocyte development and platelet production are key pathophysiological stages in ionizing radiation (IR)-induced thrombocytopenia. Protein kinase C (PKC) plays an important role in regulating megakaryocyte development and platelet production. However, it remains unclear how PKC regulates IR-induced megakaryocyte apoptosis. In this study, we found that pretreatment of PKC pan-inhibitor Go6983 delayed IR-induced megakaryocyte apoptosis, and inhibited IR-induced mitochondrial membrane potential and ROS production in CMK cells. Moreover, suppressing PKC activation inhibited cleaved caspase3 expression and reduced p38 phosphorylation levels, and IR-induced PKC activation might be regulated by p53. In vivo experiments confirmed that Go6983 promoted platelet count recovery after 21 days of 3 Gy total body irradiation. Furthermore, Go6983 reduced megakaryocyte apoptosis, increased the number of megakaryocyte and polyploid formation in bone marrow, and improved the survival rate of 6 Gy total body irradiation. In conclusion, our results provided a potential therapeutic target for IR-induced thrombocytopenia.

100 Deals associated with GO-6976

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia with FLT3/ITD Mutation	Preclinical	JP	University of Fukui	15 Apr 2012
Inflammation	Discovery	US	Parke-Davis & Co. Ltd.	-

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