CDK9 inhib 
Welcome,         Profile    Billing    Logout  
 26 Companies  20 Products   20 Products   267 Diseases   19 Trials   2308 News 


«12...56789101112131415...2122»
  • ||||||||||  AZD4573 / AstraZeneca
    Journal:  CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma. (Pubmed Central) -  Apr 4, 2023   
    Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells...Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.
  • ||||||||||  Journal:  Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition. (Pubmed Central) -  Mar 24, 2023   
    However, targeting CDK9 in the clinic has historically proven elusive, a challenge that stems from the often highly intolerable cytotoxicity attributed to its essentiality across many cell lineages and the polypharmacology of the first generation of pan-CDK inhibitors to reach the clinic. A new wave of highly selective molecules progressing through the early stages of clinical evaluation offers renewed hope.
  • ||||||||||  Verzenio (abemaciclib) / Eli Lilly
    Journal:  Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells. (Pubmed Central) -  Mar 15, 2023   
    Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p-Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl-2, and myeloid cell leukaemia-1 (Mcl-1), which was important for the anti-AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.
  • ||||||||||  alvocidib (DSP-2033) / Sumitomo Pharma, fadraciclib (CYC065) / Cyclacel
    A non-canonical CDK9 complex mediates endocycling in polyaneuploid cancer cell (PACC) state (Section 9; Poster Board #17) -  Mar 14, 2023 - Abstract #AACR2023AACR_8582;    
    Combination of CDK9 inhibition with chemotherapy showed a suppressive effect on the PACC population. Our findings therefore suggest that a non-canonical CDK9 complex could be critical role for the endocycling to access and maintain the PACC state and represents a therapeutic candidate to eliminate the resistance-mediating PACC state.
  • ||||||||||  alvocidib (DSP-2033) / Sumitomo Pharma, Zymafos (palifosfamide) / Alaunos Therap, TP-1287 / Sumitomo Pharma
    CDK9 inhibition as a potential therapeutic strategy in Ewing sarcoma (Section 9; Poster Board #13) -  Mar 14, 2023 - Abstract #AACR2023AACR_8579;    
    P1
    TP-1287 may be a potential therapeutic option for the current regimen in EWS. TP-1287 is being investigated for solid tumors including EWS (clinicaltrials.gov, NCT03604783).
  • ||||||||||  Ibrance (palbociclib) / Pfizer
    Identification of CDK15 activating cyclins by a recombinant co-expression approach (Section 9; Poster Board #9) -  Mar 14, 2023 - Abstract #AACR2023AACR_8575;    
    Since CDK inhibitors have been in the focus of interest at least since the approval of the first candidate (Palbociclib) for the treatment of ER+/HER+ breast cancer, testing the selectivity of other drug candidates within the complete group of CDKs is critically important to avoid unwanted off-target effects and toxicity...CDK15 and the respective Cyclins were co-expressed in insect cells, purified by affinity chromatography and tested for in-vitro activity using a panel of generic, broad-spectrum protein kinase substrates. We will present data on the identification of CDK15 activating Cyclins and the biochemical characterization of the in-vitro kinase activity of such CDK15/Cyclin complexes including a panel of kinase inhibitors.
  • ||||||||||  Preclinical efficacy of CDK7 inhibitor-based combinations in cellular models of advanced myeloproliferative neoplasms (MPN) (Section 20; Poster Board #23) -  Mar 14, 2023 - Abstract #AACR2023AACR_8427;    
    In an aggressive xenograft model of HEL-GFP/Luc cells in NSG mice, compared to the vehicle control, monotherapy with SY5609 significantly reduced the MPN sAML burden and improved survival of the NSG mice without causing host toxicity. These findings demonstrate promising activity and support the rationale to further evaluate the in vivo efficacy of CDK7i-based combinations against advanced MPN.
  • ||||||||||  AZD4573 / AstraZeneca
    A platform utilizing high-grade serous ovarian cancer organoids for prospective patient stratification in functional precision medicine (Room W304 A-D - Convention Center) -  Mar 14, 2023 - Abstract #AACR2023AACR_7959;    
    Importantly, the selected final hits were identified solely based on screening in organoid models from primary disease.In summary, we here demonstrate that HGSC organoids derived from primary disease material predict a majority of patient-specific drug vulnerabilities of organoids derived from the relapsed HGSC lesions. This indicates that patient stratification in functional precision medicine for treatment of HGSC relapse could be prospectively performed at the primary disease stage.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, dinaciclib (MK-7965) / Ligand, Merck (MSD)
    Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia (Section 38; Poster Board #15) -  Mar 14, 2023 - Abstract #AACR2023AACR_7079;    
    In summary, our study identified a highly synergistic drug combination, venetoclax and dinaciclib, for the treatment of hypodiploid B ALL, an aggressive leukemia with few effective current therapies. Finally, the promising results presented in this study may prompt further studies to support the inclusion of hypodiploid and other B-ALL patients to clinical trials combining phase I/II drugs against BCL-2 (mainly venetoclax) and CDK9 (dinaciclib, alvocidib, flavopiridol, SNS-032) or MCL-1 (MIK-665).
  • ||||||||||  Treatment of PTEN/PI3K co-mutated endometrial adenocarcinoma with multitarget small molecule inhibitors (Section 42; Poster Board #5) -  Mar 14, 2023 - Abstract #AACR2023AACR_5922;    
    Dual-target inhibitors LCI133 and LCI136 are nanomolar potent in AN3-CA and RL95-2 EC cell lines, suggesting a role of CDK9 inhibition of PTEN/PI3K co-mutated EC. Preliminary studies demonstrate an upregulation of MYC gene and protein expression in FBXW7mut EC but not FBXW7wt, and the role of FBXW7 as a predictive biomarker in treatment of PTEN/PIK3R1 co-mutated EC warrants further investigation.
  • ||||||||||  Design and characterization of highly potent and selective CDK9 heterobifunctional degraders (Section 44; Poster Board #19) -  Mar 14, 2023 - Abstract #AACR2023AACR_4734;    
    We carry out transcriptional and phosphoproteomics profiling to comprehensively characterize the downstream effects and cellular adaptations resulting from CDK9 degradation. We gain new insights into adaptive responses to CDK9 modulation and the biological contexts most responsive for therapeutic application.
  • ||||||||||  XNW9015 / Evopoint
    Discovery of XNW9015, a potent, selective, and CNS-penetrating covalent inhibitor of CDK7 with excellent in vivo antitumor activities (Section 31; Poster Board #3) -  Mar 14, 2023 - Abstract #AACR2023AACR_4525;    
    In the Palbociclib-resistant breast cancer cell line MCF-7, XNW9015 exhibited antiproliferative activity, with an IC50 of 81nM, while neither Palbociclib nor Fulvestrant can inhibit the cell viability...XNW9015 exhibited superior rodent pharmacokinetic characteristics when compared to LY3405105 (Eli Lilly and Company, WO2019099298)...In summary, XNW9015 has demonstrated potent in vitro and in vivo antitumor effects, favorable pharmacokinetic and toxicological properties. XNW9015 has become a potential clinical candidate for cancer therapeutics, both as monotherapies and in combination settings.
  • ||||||||||  fadraciclib (CYC065) / Cyclacel
    CDK2 inhibition & disruption of centrosome stoichiometry: a clinically tractable death program for aneuploid cancer cells (Section 15; Poster Board #3) -  Mar 14, 2023 - Abstract #AACR2023AACR_3836;    
    To elucidate engaged mechanisms focused ion beam scanning electron microscope (FIB-SEM) and immunofluorescent staining were each used to interrogate the ultrastructure of multipolar mitosis after CDK2 inhibition by CYC065-treatment (a CDK2/9 inhibitor)...This is a clinically-tractable pharmacologic mechanism that conferring cancer cell death. Current work determines if similar mechanisms are engaged in vivo in syngeneic mouse lung cancer models undergoing CDK2 antagonism.
  • ||||||||||  Zykadia (ceritinib) / Novartis, SNS-032 / Viracta Therap
    Journal:  Piperlongumine conjugates induce targeted protein degradation. (Pubmed Central) -  Feb 27, 2023   
    Mechanistically, we identified KEAP1 as the E3 ligase recruited by 955 to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
  • ||||||||||  Journal, Metastases:  CDK9 inhibitors downregulate DKK1 expression to suppress the metastatic potential of HCC cells. (Pubmed Central) -  Feb 27, 2023   
    Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML. Taken together, our findings suggest that CDK9 inhibitors are potent tools to target DKK1, which can suppress the metastatic progression of HCC.
  • ||||||||||  Biomarker, Journal:  The prognostic role of p53 and its correlation with CDK9 in urothelial carcinoma. (Pubmed Central) -  Feb 27, 2023   
    CDK9 is associated with the expression of p53, possibly through interactions with p53 inhibitors. Since the blockade of CDK9 in other malignancies reactivates wild-p53 activity, confirming the crosstalk between p53 and CDK9 in bladder cancer may be another step to explain the mechanism of tumor progression in its early stages.
  • ||||||||||  Understanding impact of linker structure on aqueous solubility and overall lipophilicity of CDK9 degraders (Hall F-H (Indiana Convention Center)) -  Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_2791;    
    New degraders are being synthesized based on these observations and are expected to deliver potent degraders that also possess excellent ex vivo-determined permeability, solubility and hepatic clearance, leading to selection of lead compounds for in vivo studies. Most importantly, this work is expected to provide valuable lessons regarding linker design for degraders that would be applicable to various degrader series for different protein targets.
  • ||||||||||  Journal:  Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma. (Pubmed Central) -  Jan 24, 2023   
    The BRD4-NUT/p300 chromatin condensation is key for activating transcription of pro-proliferation genes such as ALX1, resulting ALX1/Snail signaling and epithelial-to-mesenchymal transition. Our study provides a previously underappreciated structural mechanism illuminating BRD4-NUT's bipartite p300 recruitment and activation in NUT carcinoma that nucleates a feed-forward loop for propagating histone hyperacetylation and chromatin condensation to sustain aberrant anti-differentiation gene transcription and perpetual tumor cell growth.