NMS-1116354 / Nerviano Medical Sciences - LARVOL DELTA

Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway. (PubMed, Biomedicines) - "Importantly, PHA-767491 decreased E2F-mediated transcription of the G1/S regulators cyclin A2, cyclin E1 and cyclin E2, and this effect was independent of CDK9 inhibition. Significantly, the enhanced inhibitory profile of PHA-767491 is mediated by potent inhibition of both DDK and the CDK2-Rb-E2F transcriptional network, that provides the molecular basis for its increased anti-proliferative effects in RB cancer cell lines."

Journal • Oncology • CCNA2 • CCNE1 • CDC7 • CDK2 • MCM2

Homologous recombination technology generated recombinant pseudorabies virus expressing EGFP facilitates to evaluate its susceptibility to different cells and screen antiviral compounds. (PubMed, Res Vet Sci) - "Meanwhile, the antiviral activities of harmine and PHA767491 were also conveniently validated in vitro, as directly reflected by the reduced EGFP signals. These results demonstrate that this recombinant PRV virus should be a useful tool for basic virology researches and antiviral agent screening."

Journal • Infectious Disease

[VIRTUAL] Pharmacological targeting CDC7 sensitizes oxaliplatin treatment in colorectal cancer (AACR 2021) - "Importantly, pharmacological inhibition of CDC7 with inhibitor (XL413 or PHA767491) could overcome oxaliplatin resistance of CRC cells in cells proliferation, clone formation and tumorsphere formation. The combination of oxaliplatin and XL413 significantly inhibit xenograft tumor growth, which showed remarkably decreased Ki-67 and increased cleaved-caspase 3 by IHC analysis. Collectively, our findings unveil the critical role of CDC7 in colon cancer cells and targeting CDC7 is a potential effective therapeutic for CRC patients."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CASP3 • MCM2

Overexpression of the Msk1 Kinase in Patients With Chronic Lung Allograft Dysfunction and its Confirmed Role in a Murine Model. (PubMed, Transplantation) - "These findings suggest the overall interest of the MSK1 kinase either as a marker or as a potential therapeutic target in lung dysfunction posttransplantation."

Journal • Respiratory Diseases • Transplantation • IL6

Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles. (PubMed, Pharmaceutics) - "In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood-brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology • Proteinopathy • TARDBP

Suppression of EWS-FLI1 transcription using a combination therapy of mithramycin and cyclin-dependent kinase 9 inhibition (AACR 2018) - "...PHA-767491, a cyclin-dependent kinase 9 inhibitor (CDK9i), reverses the effect on EWS-FLI1 on several targets at both the mRNA and protein level across multiple ES cell lines when combined with MMA. We utilize matrix drug screening to identify that PHA-767491 synergizes with MMA in terms of a reduction in cell viability as measured by MTS and cell growth as measured by time-lapse microscopy... We describe an MMA-CDK9i combination that displays excellent activity against EWS-FLI1 driven transcription. We confirmed this using multiple independent assays in both in vitro and in vivo models. We complete this work with the hope that it can eventually be translated to patients."

Combination therapy • Sarcoma

Suppression of EWS-FLI1 transcription using a combination therapy of mithramycin and cyclin-dependent kinase 9 inhibition (AACR 2018) - "...PHA-767491, a cyclin-dependent kinase 9 inhibitor (CDK9i), reverses the effect on EWS-FLI1 on several targets at both the mRNA and protein level across multiple ES cell lines when combined with MMA. We utilize matrix drug screening to identify that PHA-767491 synergizes with MMA in terms of a reduction in cell viability as measured by MTS and cell growth as measured by time-lapse microscopy... We describe an MMA-CDK9i combination that displays excellent activity against EWS-FLI1 driven transcription. We confirmed this using multiple independent assays in both in vitro and in vivo models. We complete this work with the hope that it can eventually be translated to patients."

Combination therapy • Sarcoma

A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation. (PubMed, Front Immunol) - "Through a screening strategy that we have previously introduced, PHA-767491, an inhibitor of the kinases Cdc7 and Cdk9, was identified to impede TCR signaling...Inhibition of Cdc7/Cdk9 impairs T cell responses, which could potentially be detrimental for the immune response to tumors, and also compromises the ability to resist infections. The Cdc7/Cdk9 inhibitor is a strong candidate as a cancer therapeutic, but its effect on the immune system poses a problem for clinical applications."

IO Biomarker • Journal • Oncology

Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock. (PubMed, Proc Natl Acad Sci U S A) - "A prr5 toc1 double mutant was hyposensitive to PHA767491-induced period lengthening. Together, our results reveal posttranslational modification of transcriptional repressors in plant clock TTFL by CK1 family proteins, which also modulate nonplant circadian clocks."

Journal

Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases. (PubMed, J Mol Neurosci) - "Further study of SCA17 transgenic mice carrying human TBP-109Q showed that PHA-767491 ameliorated the gait ataxia and the inflammatory response both centrally and peripherally. Our findings suggest that PHA-767491 has a broad spectrum of activity in the treatment of different PAD and that this activity could be based on the anti-inflammation mechanism."

Journal

Antiviral activity of PHA767491 on Caprine alphaherpesvirus 1 in vitro. (PubMed, Res Vet Sci) - "Experiments will be necessary to assess whether PHA767491 is suitable for treatment of vaginal lesions in CpHV-1-goat model. This could provide hints for the therapy of genital alphaherpesvirus infections in humans."

Journal • Preclinical

A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy. (PubMed, Breast Cancer Res) - "Our results highlight that dual inhibition of cdc7 and CDK9 by PHA-767491 is a potential strategy for targeting TNBC resistant to EGFR-TKIs."

Journal

Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML. (PubMed, Sci Rep) - "Here we show that bone marrow mesenchymal stromal cells (BMSC) provide resistance to AML cells against BH-mimetics, cytarabine and daunorubicin, but this is not mediated by Bcl-2 and/or Bcl-X as previously thought. Importantly, the CD34/CD38 leukemic stem cell-encompassing population was equally sensitive to the combination of PHA-767491 and ABT-737. These results indicate that Bcl-2/Bcl-X and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival."

IO Biomarker • Journal

Structure-function study of a novel inhibitor of the casein kinase 1 family in Arabidopsis thaliana. (PubMed, Plant Direct) - "Using circadian period-lengthening activity as an estimation of the CK1 inhibitor effect in vivo, we performed a structure-activity relationship study of analogues of the CK1 inhibitor PHA767491 (1,5,6,7-tetrahydro-2-(4-pyridinyl)-4H-pyrrolo[3,2-c]pyridin-4-one hydrochloride)...Affinity proteomics using an AMI-331 probe showed that the targets of AMI-331 inhibition are mostly CK1 kinases. As such, AMI-331 is a potent and selective CK1 inhibitor that shows promise in the research of CK1 in plants."

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