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DRUG:

atuveciclib (BAY 1143572)

i
Other names: BAY1143572, BAY 1143572
Associations
Company:
Bayer
Drug class:
CDK9 inhibitor, P-TEFb inhibitor
Associations
3ms
Cyclin dependent kinase 9 inhibition reduced programmed death-ligand 1 expression and improved treatment efficacy in hepatocellular carcinoma. (PubMed, Heliyon)
CDK9 inhibitors AZD4573 and atuveciclib reduced the IFN-γ induced PD-L1 expression in a dose-dependent manner. In conclusion, CDK9 inhibition could reduce the expression of PD-L1 in HCC cells. Using both CDK9 inhibitors and anti-PD-L1 antibodies is more effective than using either agent alone.
Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • IFNG (Interferon, gamma) • CDK9 (Cyclin Dependent Kinase 9)
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AZD4573 • atuveciclib (BAY 1143572)
9ms
Cyclin-Dependent kinase 9 (CDK9) inhibitor Atuveciclib ameliorates Imiquimod-Induced Psoriasis-Like dermatitis in mice by inhibiting various inflammation factors via STAT3 signaling pathway. (PubMed, Int Immunopharmacol)
Moreover, Atuveciclib interfered with the abnormal STAT3 signaling pathway through the inhibition of CDK9, which ultimately ameliorated psoriatic-like skin inflammation. These suggested that CDK9 inhibition is a potential strategy for batting psoriasis.
Preclinical • Review • Journal
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IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • CDK9 (Cyclin Dependent Kinase 9)
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Zyclara (imiquimod) • atuveciclib (BAY 1143572)
1year
Unraveling TIMP1: a multifaceted biomarker in colorectal cancer. (PubMed, Front Genet)
Drug sensitivity analysis, conducted using the DepMap database, revealed that colorectal cancer cell lines exhibiting elevated levels of TIMP1 expression were more responsive to certain drugs, such as CC-90003, Pitavastatin, Atuveciclib, and CT7001, compared to those with low levels of TIMP1. Furthermore, TIMP1 expression was positively correlated with that of ferroptosis-related genes, such as GPX4 and HSPA5. TIMP1 can be used as a biomarker for colorectal cancer and is associated with the immunological microenvironment, drug sensitivity, and ferroptosis inhibition in this disease.
Journal • IO biomarker
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CXCL8 (Chemokine (C-X-C motif) ligand 8) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • SPP1 (Secreted Phosphoprotein 1) • GPX4 (Glutathione Peroxidase 4) • TIMP1 (Tissue inhibitor of metalloproteinases 1) • HSPA5 (Heat Shock Protein Family A (Hsp70) Member 5) • MMP1 (Matrix metallopeptidase 1) • CXCL1 (Chemokine (C-X-C motif) ligand 1) • MMP3 (Matrix metallopeptidase 3)
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TIMP1 overexpression • KIM1 expression • TIMP1 expression
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samuraciclib (CT7001) • CC-90003 • atuveciclib (BAY 1143572) • pitavastatin
over1year
Cyclin dependent kinase 9 (CDK9) inhibition increased efficacy of programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma (HCC) through decreasing programmed death-ligand 1 (PD-L1) expression (AACR 2023)
We thus examined the influence of CDK9 inhibition on the expression of PD-L1 in HCC and the potential of improving the efficacy of PD-1 blockade with the combination of CDK9 inhibitors. We first examined the influence of specific CDK9 inhibitors, AZD4573 and atuveciclib, on interferon-γ (IFN-γ) induced PD-L1 expression of human HCC cell lines HuH7 and Hep3B. We demonstrated that CDK9 inhibition could reduce the IFN-γ induced PD-L1 expression of HCC cells. Combination of CDK9 inhibitors and anti-PD-L1 antibodies was more effective than either therapy alone.
Clinical • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • IFNG (Interferon, gamma) • CDK9 (Cyclin Dependent Kinase 9)
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PD-L1 expression • IFNG expression • CDK9 overexpression
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AZD4573 • atuveciclib (BAY 1143572)
2years
Cyclin Dependent Kinase 9 Inhibition as a Potential Treatment for Hepatocellular Carcinoma. (PubMed, Oncology)
We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • BIRC5 (Baculoviral IAP repeat containing 5) • CDK9 (Cyclin Dependent Kinase 9)
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MYC expression • CDK9 overexpression
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AZD4573 • atuveciclib (BAY 1143572)
over2years
VIP152 IS A NOVEL CDK9 INHIBITOR WITH IMPROVED SELECTIVITY, TARGET MODULATION, AND CARDIAC SAFETY IN PATIENTS WITH LYMPHOMA (EHA 2022)
To demonstrate the utility of a selective CDK9 inhibitor for treatment of hematologic patients with an unmet medical need such as high-grade B cell lymphoma (HGBL) and chronic lymphocytic leukemia who relapse or are refractory to ibrutinib and venetoclax (R/R CLL)...Differential expression (DE) analysis from VIP152, atuveciclib and KB-0742 treatment of 2 lymphoma cell lines by RNA seq is compared to DE of samples from 7 VIP152 treated HGBL patients...With high ATP, VIP152, AZD4573 and alvocidib maintain potency in low nM range, while fadraciclib and KB-0742 have 760 nM-1.7 µM IC50s...Selective transcriptional downregulation is observed with 30mg IV weekly. Samples from patients with DLBCL or CLL are sensitive to VIP152 and updated PK, PD and ctDNA dynamics from the ongoing phase 1 trials (NCT02635672, NCT04978779) will be presented.
Clinical
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 R175H • TP53 R248Q
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • alvocidib (DSP-2033) • istisociclib (KB-0742) • fadraciclib (CYC065) • enitociclib (VIP152) • AZD4573 • atuveciclib (BAY 1143572)
almost3years
The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death. (PubMed, Anticancer Res)
This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.
Journal
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MCL1 (Myeloid cell leukemia 1) • CFLAR (CASP8 and FADD-like apoptosis regulator)
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gemcitabine • atuveciclib (BAY 1143572)
4years
Anti-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia. (PubMed, Ther Adv Hematol)
Here, we investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7, which may contribute to decreased MYC and MCL1 protein levels. Finally, the combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent-based treatment of T-PLL.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7)
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Venclexta (venetoclax) • atuveciclib (BAY 1143572)
4years
CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. (PubMed, Cell Death Dis)
Small-molecule drugs targeting the CDK9 kinase, dinaciclib, flavopiridol, roscovitine, AT-7519, SNS-032, and DRB, diminished MDM4 levels and activated p53 in A375 melanoma and MCF7 breast carcinoma cells with only a limited effect on MDM2...CDK9 inhibitor atuveciclib downregulated MDM4 and enhanced p53 activity induced by nutlin-3a, an inhibitor of p53-MDM2 interaction, and synergized with nutlin-3a in killing A375 melanoma cells. Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4.
Journal
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MDM4 (The mouse double minute 4)
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alvocidib (DSP-2033) • SNS-032 • dinaciclib (MK-7965) • Nutlin-3 • AT7519 • atuveciclib (BAY 1143572)
5years
Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov)
P1; N=80; Active, not recruiting; Sponsor: Bayer; Recruiting --> Active, not recruiting; N=184 --> 80; Trial primary completion date: Feb 2017 --> Aug 2016
Trial primary completion date • Enrollment change • Enrollment closed • Clinical
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PCNA (Proliferating cell nuclear antigen)
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MYC expression • PCNA expression
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atuveciclib (BAY 1143572)
5years
Enrollment change • Clinical
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PCNA (Proliferating cell nuclear antigen)
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MYC expression • PCNA expression
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atuveciclib (BAY 1143572)
5years
Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (clinicaltrials.gov)
P1; N=280; Recruiting; Sponsor: Bayer; N=146 --> 280; Trial primary completion date: Jun 2016 --> Feb 2017
Trial primary completion date • Enrollment change • Clinical
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PCNA (Proliferating cell nuclear antigen)
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MYC expression • PCNA expression
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atuveciclib (BAY 1143572)