bisindolylmaleimide IX (RO-31-8220) / Roche - LARVOL DELTA

Ro 31-8220 suppresses bladder cancer progression via enhancing autophagy in vitro and in vivo. (PubMed, FEBS Open Bio) - "Blockade of autophagy with chloroquine, an autophagy inhibitor, attenuated Ro-31-8220 induced bladder cancer cell death. These results suggest that Ro-31-8220 may be a novel promising candidate drug for bladder cancer therapy. Further studies, including clinical trials, are required to validate these results."

Journal • Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

High glucose mediates diabetic peripheral neuropathy by inducing Schwann cells apoptosis through the Dgkh/PKC-α signaling pathway. (PubMed, Acta Diabetol) - "Dgkh expression increased under HG conditions and triggered apoptosis of HSCs, boosting DPN via inhibiting PKC-α."

Journal • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Pain • Peripheral Neuropathic Pain

Decoding atypical teratoid rhabdoid tumor subtype-specificity: single cell aspect of differentiation trajectories and potential maturation therapy (EACR 2025) - "Our study decodes ATRT subtype-specificity at single cell level and reveals that each ATRT subtype is enriched for distinct signaling trajectories mirroring normal fetal brain development, enabling the development of maturation therapies tailored towards ATRTs."

Brain Cancer • CNS Tumor • Oncology • Pediatrics • Rhabdoid Tumor • Sarcoma • SMARCA4 • SMARCB1

Application of Fluorescence- and Bioluminescence-Based Biosensors in Cancer Drug Discovery. (PubMed, Biosensors (Basel)) - "These biosensors have enabled breakthrough discoveries, including the identification of Celastrol as a novel YAP-TEAD inhibitor through NanoBiT-based screening, and the development of TR-FRET assays that successfully identified Ro-31-8220 as a SMAD4R361H/SMAD3 interaction inducer...Emerging trends are discussed, including integrating artificial intelligence and advanced nanomaterials for enhanced biosensor performance. In conclusion, this review offers a comprehensive analysis of fluorescence- and bioluminescence-based biosensor applications in the dynamic cancer drug discovery field, presenting quantitative evidence of their impact and highlighting their potential to revolutionize targeted cancer treatments."

Journal • Review • Oncology • Targeted Protein Degradation • SMAD3

Modified Lipoprotein-induced sFlt1 Production in Human Placental Trophoblasts is Mediated by Protein Kinase C. (PubMed, Eur J Pharmacol) - "Modified lipoproteins upregulate sFlt1 in trophoblasts via a PKC-mediated mechanism, involving at least α and β isoforms. The data suggest potential therapeutic targets to reduce the risk of preeclampsia in women with diabetes."

Journal • Diabetes • Dyslipidemia • Gynecology • Metabolic Disorders • FLT1 • PRKCB

Epoxytiglianes induce keratinocyte wound healing responses via classical protein kinase C activation to promote skin re-epithelialization. (PubMed, Biochem Pharmacol) - "The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors...PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51-151 nM. PKC-α inhibitor, Ro 31-8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses...Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin."

Journal • Oncology • CCNB1 • CDKN1A • KRT17 • MMP1 • MMP10 • MMP7 • PRKCB

Simulation of molecular glue-induced ternary complexes by computational methods and protein NMR (ACS-Fall 2024) - "By employing this approach, we are able to recapitulate the restored PPIs between mutant SMAD4_R361H and SMAD3, which are induced by a small molecule (bisindolylmaleimide IX). Our methodology offers a comprehensive and adaptable approach, designed to identify and refine MG with nuanced mechanisms that may not be immediately apparent, thus likely expediting and enriching future endeavors in MG drug discovery."

Targeted Protein Degradation • SMAD3

Interactive mechanism between connexin43 and Cd-induced autophagic flux blockage and gap junctional intercellular communication dysfunction in rat hepatocytes. (PubMed, Heliyon) - "To establish an in vitro model of Cd-induced hepatocyte injury, the Buffalo rat liver 3A cell line (BRL3A) was utilized.In order to elucidate the mechanism by which Cx43 influences Cd-induced hepatocyte toxic injury, inhibitors of Cx43 (Dynasore) and P-Cx43 (Ro318220) were employed in the model...The down-regulation of Cx43 expression was found to worsen the morphological damage induced by cadmium exposure, diminish the cell proliferation capacity of BRL3A cells, and exacerbate the disruption of GJIC and autophagic flow caused by Cd.These findings suggest that Cx43 may serve as a potential therapeutic target for the treatment of liver damage resulting from Cd exposure. By targeting Cx43, it may be possible to mitigate the adverse effects of Cd on hepatocytes."

Journal • Preclinical • Hepatology • GJA1

The rapid activation of cPKCβII by progesterone results in the negative regulation of Ca 2+ influx in human resting T cells. (PubMed, J Chin Med Assoc) - "Nongenomic membrane activation of cPKCβII by progesterone causes immunosuppression via negative regulation of Ca 2+ influx into human resting T cells. This prevents resting T cell activation and proliferation, which protects the fetus from maternal immune attack while decreasing maternal autoimmune disease flare-ups during pregnancy. Thus, cPKCβII modulators might provide a new therapeutic approach to balancing T cell tolerance and immunity."

Journal • Immunology • PRKCB

β-amyloid peptide Aβ40 stimulates glycoprotein receptor GPVI signaling to generate procoagulant platelets (ISTH 2023) - "We found that platelet stimulation with the Aβ40 peptide rapidly induced platelet aggregation and potentiated platelet aggregation in response to sub-threshold stimulation with the GPVI agonist crosslinked collagen-related peptide (CRP-XL). Platelet aggregation in response to Aβ40 peptide was abrogated by inhibition of ADP release with exogenous apyrase as well as the integrin blocker, eptifibatide. Inhibitors of platelet ITAM signaling also prevented platelet aggregation following Aβ40 stimulation, including the BTK inhibitor ibrutinib and the protein kinase C (PKC) inhibitor Ro 31-8220."

Alzheimer's Disease • CNS Disorders

Identification of potential biomarkers and immune infiltration characteristics in recurrent implantation failure using bioinformatics analysis. (PubMed, Front Immunol) - "Finally, we used cMap analysis to identify potential therapeutic or induced compounds for RIF, among which fulvestrant (estrogen receptor antagonist), bisindolylmaleimide-ix (CDK and PKC inhibitor), and JNK-9L (JNK inhibitor) were thought to influence the pathogenic process of RIF. Furthermore, our findings revealed the level of immune infiltration in RIF by highlighting three signaling pathways (Wnt/-catenin signaling, Notch signaling, and immune response) and three potential diagnostic DEGs (AKT1, PSMB8, and PSMD10). Importantly, our findings may contribute to the scientific basis for several potential therapeutic agents to improve endometrial receptivity."

Biomarker • Journal • AKT1 • PSMB8 • PSMD10

Commiphora myrrha stimulates insulin secretion from β-cells through activation of atypical protein kinase C and mitogen-activated protein kinase. (PubMed, J Ethnopharmacol) - "Our data indicate that CM directly stimulates insulin secretion through activating known downstream effectors of insulin-stimulus secretion coupling. Indeed, the increase in insulin secretion seen with CM is independent of changes in [Ca] and does not involve activation of VGCC. Instead, the CM stimulatory effect on insulin secretion is completely dependent on protein kinase activation. Our findings indicate that CM could induce insulin exocytosis by stimulating the phosphorylation and activation of PKCζ, which in turn phosphorylates and activates ERK1/2."

Journal • Diabetes • Metabolic Disorders • Neuroendocrine Tumor • Solid Tumor

PKCβ Inhibition Promotes TXNIP Degradation to Ameliorate Pancreatic β-Cell Dysfunction. (PubMed, Pharmacology) - "This study reveals the regulating mechanism of PKCβ inhibitor on TXNIP degradation to improve β-cell dysfunction. These data indicated PKCβ inhibitor is a promising agent for ameliorating β-cell dysfunction through TXNIP."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • PRKCB • TXNIP

SS18-SSX drives CREB activation in synovial sarcoma. (PubMed, Cell Oncol (Dordr)) - "In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies."

IO biomarker • Journal • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • BCL2 • BCL2L1 • CCND1 • PCNA • SS18

Signaling Pathway of Histamine H Receptor-Mediated Histamine H Receptor Gene Upregulation Induced by Histamine in U-373 MG Cells. (PubMed, Curr Issues Mol Biol) - "Histamine-induced H1R gene upregulation was inhibited by H1R antagonist d-chlorpheniramine, but not by ranitidine, ciproxifan, or JNJ77777120, and H2R, H3R, or H4R antagonists, respectively. Ro-31-8220 and Go6976 also suppressed this upregulation, however, the PKCδ selective inhibitor rottlerin and the PKCβ selective inhibitor Ly333531 did not...These data suggest that the H1R-activated H1R gene expression signaling pathway in U-373 MG cells is different from that in HeLa cells, possibly by using different promoters. The involvement of PKCα also suggests that compounds that target PKCδ could work as peripheral type H1R-selective inhibitors without a sedative effect."

Journal • PRKCB

Neuroprotective Role of the B Vitamins in the Modulation of the Central Glutamatergic Neurotransmission. (PubMed, CNS Neurol Disord Drug Targets) - "Therefore, these B vitamins may reduce the strength of glutamatergic synaptic transmission and is of considerable importance as potential targets for therapeutic agents in glutamate-induced excitation-related diseases."

Journal • CNS Disorders • Depression • Psychiatry • CACNA1B

Modulation of the rat angiotensin type 1a receptor by an upstream short open reading frame. (PubMed, Peptides) - "Ang II-induced ERK1/2 activation was completely inhibited by the protein kinase C (PKC) inhibitor Ro 31-8220 regardless of whether the sORF was intact or disrupted. Flow cytometric analyses suggested the intact sORF improved cell survival; the percentage of live cells increased (p < 0.05) while the percentage of early apoptotic cells decreased (p < 0.01) in cells transfected with the ATR plasmid containing the intact sORF. These findings have implications for the regulation of ATRs in physiological and pathological conditions and warrant investigation of sORFs in the 5' leader sequence (5'LS) of other GPCRs."

Journal • Preclinical

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays. (PubMed, Methods) - "Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Hypomorph Mutation-Directed Small-Molecule Protein-Protein Interaction Inducers to Restore Mutant SMAD4-Suppressed TGF-β Signaling. (PubMed, Cell Chem Biol) - "Ro-31-8220 reactivated the dormant SMAD4-mediated transcriptional activity and restored TGF-β-induced tumor suppression activity in SMAD4 mutant cancer cells. Thus, demonstration of Ro-31-8220 as a SMAD4/SMAD3 interaction inducer illustrates a general strategy to reverse the lost function of tumor suppressors with hypomorph mutations and supports a systematic approach to develop small-molecule protein-protein interaction (PPI) molecular glues for biological insights and therapeutic discovery."

Journal • Oncology • Targeted Protein Degradation • SMAD4

Taurine Attenuates Streptococcus uberis-Induced Bovine Mammary Epithelial Cells Inflammation via Phosphoinositides/Ca Signaling. (PubMed, Front Immunol) - "In order to investigate whether taurine regulates inflammation by means of PIs/ Ca systems, competitive inhibitors of taurine (β-alanine) siTauT, siPAT1, siPLC, siCaN, siPKC, and inhibitors of PLC (U73122), PKC (RO31-8220), and CaN (FK 506) were used...Both the Ca-PKCα-NF-κB, and Ca-CaM-CaN-NFAT signaling pathways of S. uberis infection and the regulatory roles of taurine follow activation of PIs/Ca systems. These data increase our understanding on the mechanisms of multifunctional nutrient, taurine attenuated inflammatory responses caused by S. uberis infection, and provide theoretical support for the prevention of this disease."

Journal • Immunology • Inflammation

Updates on the surface antigens of basophils: CD16 on basophils of patients with respiratory or insect venom allergy and the rejection of CD203c and CD63 externalization decoupling by bisindolylmaleimides. (PubMed, Clin Exp Allergy) - "We employed two PKC inhibitors, bisindolylmaleimide II and Ro 31-8220 at their supraoptimal concentrations and, after difficulties reproducing previously published data, we analyzed the fluorescence of these inhibitors alone...The inclusion of ?CD16 in negative selection cocktails selects against a subset of basophils that are CD16 or CD16 . Using CD16 basophils and unstained leukocytes, we show that previous studies with supraoptimal concentrations of bisindolylmaleimides are likely flawed and are not associated with the differential expression of CD203c and CD63."

Clinical • Journal • Allergy • Immunology