CRT0066101 / Cancer Research UK - LARVOL DELTA

Protein Kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions. (PubMed, Mol Metab) - "Using β-cell-specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity...Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet-induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • SOD2

Activation of the Piezo1 channel stimulates protein kinase D and migration in human aortic endothelial cells. (PubMed, Am J Physiol Cell Physiol) - "Treatment of ECs with CRT0066101 prevented HDAC7 phosphorylation and migration of these cells induced by Yoda1, suggesting that Yoda1-stimulated Piezo1 promotes EC migration through a PKD. Our results identify PKD as a novel downstream mediator of effects produced by agonist-induced activation of the Piezo1 mechanosensitive channel in ECs."

Journal • HDAC7

Targeting adipocyte differentiation with CRT0066101: activation of AMPK signaling in 3T3-L1 cells. (PubMed, Front Pharmacol) - "Network pharmacology analysis further supported the involvement of AMPK in CRT's anti-adipogenic action. These findings identify CRT as a novel modulator of adipocyte differentiation through AMPK activation and highlight its potential as a therapeutic candidate for obesity and metabolic syndrome."

Journal • Genetic Disorders • Metabolic Disorders • Obesity • PPARG

Deciphering the transcriptional alterations in high grade serous ovarian cancer upon catalytic inactivation of protein kinase D. (PubMed, Int J Biol Macromol) - "Collectively, our results showed that PKD and its downstream targets positively drive several tumorigenesis-associated cellular/physiological functions and could be therapeutically targeted against a lethal pathology like HOSOC."

Journal • Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation

Deciphering the transcriptional alterations in high grade serous ovarian cancer upon catalytic inactivation of protein kinase D. (PubMed, Int J Biol Macromol) - "Collectively, our results show that PKD and its downstream targets positively drive several tumorigenesis-associated cellular/physiological functions and could be therapeutically targeted against a lethal pathology like HOSOC."

Journal • Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation

Inhibition of protein kinase D and its substrate phosphatidylinositol-4 kinase III beta blocks common human coronavirus replication. (PubMed, Microbiol Spectr) - "Specifically, we found that the PKD-silencing siRNA and the PKD inhibitor CRT0066101 have broad-spectrum antiviral activity against HCoV-OC43, HCoV-NL63, and HCoV-229E in cultured cells...Importantly, PI4KIIIβ inhibitors also blocked human coronavirus replication. Thus, PKD may represent a promising therapeutic target against both current circulating and future emerging coronaviruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Pharmacological inhibition of protein kinase D2/Aurora kinase A signalling axis suppresses G2/M cell cycle progression and proliferation of epithelial ovarian cancer cells. (PubMed, Pathol Res Pract) - "We show that PKD2 is activated during G2/M cell cycle transition and its catalytic inactivation by small molecule inhibitor CRT0066101 or genetic knockdown caused suppression of EOC cell proliferation followed by a delay into mitotic entry...Moreover, pharmacological inhibition of Aurora kinase A by small molecule CD532 or its shRNA-mediated genetic knockdown suppressed EOC cell proliferation, induced G2/M cell cycle arrest and mitotic catastrophe followed by apoptosis. Taken together, our results indicated that PKD2 positively regulates Aurora kinase A during G2/M cell cycle entry and pharmacological targeting of PKD2/Aurora kinase A signalling axis could serve as a novel therapeutic intervention against a lethal pathology like EOC."

Journal • Colorectal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • AURKA • FBXW7 • FCGR2A • FCGR2B

Role of protein kinase D1 in vasoconstriction and haemodynamics in rats. (PubMed, Microvasc Res) - "PKD1 may play roles in aorta contraction and haemodynamics via phosphorylation of MYPT1 and actin polymerization in a calcium-independent manner."

Journal • Preclinical • PKD1 • PRKD1

Targeting PKD2 aggravates ferritinophagy-mediated ferroptosis via promoting autophagosome-lysosome fusion and enhances efficacy of carboplatin in lung adenocarcinoma. (PubMed, Chem Biol Interact) - "We found PKD2 was highly expressed in LUAD and silencing PKD2 could promote erastin-induced reactive oxygen species (ROS), malondialdehyde (MDA) accumulation, intracellular iron content and LUAD cells death...PKD2 knockdown or pharmacological inhibition by CRT0066101 could enhance efficacy of carboplatin in LUAD via ferroptosis and apoptosis. Collectively, our study revealed that abrogation of PKD2 could aggravate ferritinophagy-mediated ferroptosis by promoting autophagosome-lysosome fusion and enhance efficacy of carboplatin in LUAD. Targeting PKD2 to induce ferroptosis may be a promising strategy for LUAD therapy."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PKD2 • SQSTM1 • TFEB

Pharmacological inhibition of protein kinase D suppresses epithelial ovarian cancer via MAPK/ERK1/2/Runx2 signalling axis. (PubMed, Cell Signal) - "Mechanistically, PKD2 and PKD3 positively regulated Runx2 via MAPK/ERK1/2 pathway and promoted EOC. Taken together, our results indicated that PKD2/3/ERK1/2/Runx2 signalling axis might be a novel drug target against EOC and CRT0066101 could be developed as a promising therapeutic choice against this lethal pathology."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • PKD2 • PKD3 • RUNX2 • SPP1

Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury. (PubMed, Int Immunopharmacol) - "CRT0066101 also reduced NLRP3 activation, inhibited the assembly of the inflammasome complex, and attenuated inflammatory cell infiltration and lung tissue damage. Taken together, our data indicate that CRT0066101 exerts anti-inflammatory effects on LPS-induced inflammation through the TLR4/MyD88 signaling pathway, suggesting that CRT0066101 may have therapeutic value in acute lung injury and other MyD88-dependent inflammatory diseases."

Cytokine storm • Journal • Preclinical • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • IL1B • IL6 • MYD88 • NF-κβ • NLRP3 • TLR4 • TNFA

Loss of Protein Kinase D2 Activity Protects Against Bleomycin-Induced Dermal Fibrosis in Mice. (PubMed, Lab Invest) - "Corroboratively, pharmacologic inhibition of PKD by CRT0066101 also significantly blocked BLM-induced dermal fibrosis and reduced α-smooth muscle actin, collagen, and interleukin-6 expression. We have further identified Akt as a major downstream target of PKD2 in the early inflammatory phase of the fibrotic process. Taken together, our findings indicate that PKD2 promotes dermal fibrosis via regulating immune cell infiltration, cytokine production, and downstream activation of Akt in lesional skin, and targeted inhibition of PKD2 may benefit the treatment of this condition."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • Scleroderma • Systemic Sclerosis • IL6 • TGFB1

Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids. (PubMed, Am J Physiol Cell Physiol) - "Other lipophilic statins, including simvastatin, atorvastatin and fluvastatin also prevented PKD activation in a dose-dependent manner...Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds) and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells."

Journal • Preclinical • HDAC5 • PKD1 • PKD3 • PRKD1

Protein kinase D2 and 3 promote prostate cancer cell bone metastasis by positively regulating Runx2 in a MEK/ERK1/2-dependent manner. (PubMed, Am J Pathol) - "Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 play an important role in the bone metastasis of prostate cancer cells, and their inhibition may be beneficial for the treatment of advanced stages of prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • RUNX2

A Protein Kinase D Inhibitor Suppresses AKT on T cells and Antagonizes Cancer Immunotherapy by Anti-PD-1. (PubMed, Int Immunol) - "We report that CRT0066101, a PKD inhibitor (PKDi) suppressed growth of mouse tumor at sub-micromolar concentration in vitro...In conclusion, PKD is fundamentally required for T-cell reactivation by anti-PD-1, therefore inhibition of PKD is not appropriate for combination therapy with anti-PD-1. On the other hand, a single dose of PKDi was shown to strongly suppress experimental autoimmunity in mice, indicating that PKDi could be useful for treatment of immune related adverse events, that are frequently reported in anti-PD-1 therapy."

Journal • Immune Modulation • Immunology • Inflammation • Oncology

Protein kinase D: A therapeutic target in experimental alcoholic pancreatitis. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "PKD mediates effect of alcohol abuse on pathological process of pancreatitis and constitutes a novel therapeutic target to treat this disease."

IO biomarker • Journal • Immunology • Inflammation • Pancreatitis • BCL2 • PRSS1

TARGETING PROTEIN KINASE D IN ALCOHOLIC PANCREATITIS (DDW 2022) - "Inhibition of PKD by small molecule PKD inhibitor CID755673 or CRT0066101 markedly decreased NF-κB activation and attenuated the inflammatory and cell necrosis responses in a model of alcoholic pancreatitis...PKD3Δpanc mice had markedly decreased serum amylase and lipase activation, pancreatic NF-κB and trypsinogen activation, and mRNA expression of multiple inflammatory molecules including interleukins IL-6 and IL-1β, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α). Conclusion : With PKD3Δpanc mouse model, we further demonstrated that PKD plays a critical role in pathobiological process of alcoholic pancreatitis and PKD constitutes a novel therapeutic target to treat this disorder."

Gastrointestinal Disorder • Immunology • Inflammation • Oncology • Pancreatitis • CCL2 • IL1B • IL6 • PDX1 • PKD1 • PRKD1 • PRSS1 • TNFA

Histone deacetylase 5 is a phosphorylation substrate of protein kinase D in osteoclasts. (PubMed, Bone) - "The inhibitory effect of CRT0066101 was reduced in Hdac5 KO osteoclasts. Together these data indicate that the PRKD/HDAC5 axis contributes to osteoclast formation in vitro and suggest that this pathway may contribute to regulation of skeletal dynamics in vivo."

Epigenetic controller • Journal • HDAC4 • HDAC5

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation. (PubMed, PLoS One) - "Although PKD and NLRP3 become functionally interconnected during NLRP3 activation, the promiscuous reactivity of PKD challenges its potential use for tracing the NLRP3 inflammasome pathway."

Biomarker • Journal • Immunology • Inflammation • IL1B • NLRP3

[VIRTUAL] ALCOHOL-INDUCED EFFECTS ON PROTEIN KINASE D PROMOTE NF-ΚB ACTIVATION AND INFLAMMATORY RESPONSES IN RAT ALCOHOL-INDUCED EXPERIMENTAL PANCREATITIS (DDW 2021) - "Pretreatments with novel PKD inhibitors CID755673 (CID) and CRT0066101(CRT) significantly attenuated the severity of cerulein-induced pancreatitis... With pharmacological approach, we demonstrated that alcohol treatment enhanced NF-κB activation and inflammatory responses in alcohol-induced pancreatitis at least in part by augmenting PKD1 expression and activation. Inhibition of PKD markedly decreased NF-κB activation and attenuated the inflammatory responses in a model of alcoholic pancreatitis. The results suggest that PKD is a potential molecular target for therapy of alcohol-induced pancreatitis."

Preclinical • Inflammation • Pancreatitis • CCL2 • IL1B • IL6 • PRKD1 • TNFA

Developments in the discovery and design of Protein Kinase D inhibitors. (PubMed, ChemMedChem) - "The focus extends from broad-spectrum kinase inhibitors used in PKD signaling experiments to intentionally developed, bioactive PKD inhibitors. Finally, attention is paid to PKD inhibitors that have been identified as an off-target through large kinome screening panels."

Journal • Oncology

Inhibition Lysosomal Degradation of Clusterin by Protein Kinase D3 Promotes Triple-Negative Breast Cancer Tumor Growth. (PubMed, Adv Sci (Weinh)) - "Finally, secreted CLU (sCLU) is found to be elevated in serums from TNBC patients and reduced in serum from TNBC murine models post OGX-011 and/or CRT0066101 treatment, suggesting serum sCLU is a promising blood-based biomarker for clinical management of TNBC. Taken together, this study provides a thorough molecular basis as well as preclinical evidences for targeting CLU pathway as a new promising strategy against TNBC via revealing PRKD3 as the key regulator of CLU in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CLU

Regulation of Osteoclast Differentiation at Multiple Stages by Protein Kinase D Family Kinases. (PubMed, Int J Mol Sci) - "We show that PKD inhibitors CRT0066101 and CID755673 inhibit several distinct aspects of osteoclast formation...Treating post-fusion multinucleated osteoclasts with the inhibitors disrupted the osteoclast actin belts and impaired their resorptive activity. In conclusion, these data implicate PKD kinases as positive regulators of osteoclasts, which are essential for multiple distinct processes throughout their formation and function."

Journal • CNS Disorders • Osteoporosis

Platelets-released insulin-like growth factor 1 is correlated with anxiety in myocardial infarction. (PubMed, Biochem Biophys Res Commun) - "Anxiety is exacerbated in MI via endothelial damage-induced platelets granule releasing-mediated IGF1."

Journal • Cardiovascular • Coronary Artery Disease • Mood Disorders • Myocardial Infarction

Protein kinase D1 inhibition interferes with mitosis progression. (PubMed, J Cell Physiol) - "We found that although PKD1 overexpression did not affect mitosis progression, suppression of its catalytic activity by two structurally unrelated inhibitors (kb NB 142-70 and CRT 0066101) induced a significant delay in metaphase to anaphase transition time. PKD1 inhibition during mitosis also produced the appearance of abnormal spindles, defects in chromosome alignment, and segregation as well as apoptosis. Thus, these observations indicate that PKD1 activity is associated with mitosis regulation."

Journal • Oncology