- |||||||||| Cabometyx (cabozantinib tablet) / Exelixis, dactolisib (RTB101) / Adicet Bio
Novel Machine Learning Approaches Tailored to Protein Configuration Predict Drug Vulnerabilities in Myeloid Neoplasia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4307;
FLT3-TKD but not ITD showed higher sensitivity to cabozantinib while NRAS-Q61 to dactolisib (PI3K/mTOR dual inhibitor)...This algorithm was then used in our ongoing confirmatory drug screen collection that mimics real life application in a clinical setting. In summary, incorporation of protein configuration in drug response prediction might help unveiling unsuspected vulnerability profiles in MN addicted to specific gene mutations.
- |||||||||| Inhibiting Tumor Cell CDK9 Reprograms Cell Death Pathways to Enhance Efficacy of CAR T Cell Therapy (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3677;
Our findings demonstrate that CDK9-i-priming may potentiate elimination of tumor cells lacking specific antigen through a mechanism of enhanced bystander effect. In summary, combined CDK9-i treatment and CAR T cell therapy may have significant and broad implications in improving the efficacy of cellular immunotherapy against cancer.
- |||||||||| Inhibition of Cyclin-Dependent Kinase 9 Rapidly Induces Apoptosis in Acute Lymphoblastic Leukemia and Shows Synergistic Activity with BH3-Mimetics (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2538;
Using the multi-CDK inhibitor dinaciclib, which targets CDK1, 2, 5 and 9, and the specific CDK9 inhibitor AZD4573, we analyzed the effects of both inhibitors in a series of ALL cell lines (BCP-ALL n=10, T-ALL n=6) and primary, patient-derived xenograft (PDX) samples (BCP-ALL n=15, T-ALL n=9)...Based on this, we investigated combinatorial inhibition of CDK9 (AZD4573) together with inhibitors of BCL-2 or BCL-XL (venetoclax, A-1331852, AZD4320) using dose-response matrix analyses and found enhanced cell death and synergistic activity for both combinations...However, intrinsic insensitivity due to dysbalanced protein levels of pro-survival proteins might limit efficacy. Combining CDK9 inhibition with inhibitors of the anti-apoptotic molecules BCL-2/BCL-XL significantly enhances cell death, thus overcoming insensitivity and providing an effective, novel therapeutic anti-ALL strategy to be further evaluated for clinical application.
- |||||||||| HEXIM1 Regulates Early Erythropoiesis and Participates in Multiple Complexes in Erythroid Cells (Room 6DE (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2395;
RNA FISH (fluorescence in-situ hybridization) demonstrated co-localization of HEXIM1 with the short isoform of the essential paraspeckle RNA NEAT1 in both HUDEP2 cells and CD34+ derived erythroblasts, validating HEXIM1 presence in paraspeckles. Together these data indicate that HEXIM1 plays essential roles both in early erythropoiesis and in terminal erythroid maturation by utilizing multiple mechanisms to regulate stage-specific gene transcription.
- |||||||||| zemirciclib (AZD4573) / AstraZeneca
CDK9 Is a Vulnerability in GATA-3 Driven and MCL-1 Independent T-Cell Lymphomas (Pacific Ballroom Salons 15-17 (Marriott Marquis San Diego Marina)) - Nov 6, 2024 - Abstract #ASH2024ASH_1950;
Methods : A pharmacologic strategy, using the selective CDK9 inhibitor AZD4573, was utilized to identify CDK9 dependent transcripts...Furthermore, CDK9 and GATA-3 are binding partners, and CDK9 inhibition significantly impaired transcription of the GATA-3 dependent transcriptome. Therefore, CDK9 inhibition, by impairing expression of the GATA-3 dependent transcriptome, is an attractive therapeutic strategy for GATA-3 driven TCL, many of which are largely resistant to conventional chemotherapeutic approaches.
- |||||||||| etomoxir (MIQ-001) / Numiera Therapeutics
Integrating Metabolomics and Molecular Pathways to Uncover Therapeutic Vulnerabilities in Richter's Transformation (Pacific Ballroom Salons 15-17 (Marriott Marquis San Diego Marina)) - Nov 6, 2024 - Abstract #ASH2024ASH_1676;
Moreover, MGA KO cells showed decreased maximal respiration when treated with etomoxir, a fatty-acid oxidation inhibitor, indicating their reliance on lipid substrates...Our studies reveal Gro3P as a metabolite driver of OXPHOS in MGA KO RT via the Mga-Myc-Nme1-Pgp axis. Combining glycerolipid metabolism and OXPHOS targeting may offer effective strategies to conquer RT.
- |||||||||| Journal: MOF-mediated acetylation of CDK9 promotes global transcription by modulating P-TEFb complex formation. (Pubmed Central) - Nov 1, 2024
Notably, MOF-mediated acetylation of CDK9 at K35 promotes the formation of the P-TEFb complex through stabilizing CDK9 protein and enhancing its association with cyclin T1, which further increases RNA polymerase II serine 2 residues levels and global transcription. Our study reveals for the first time that MOF promotes global transcription by acetylating CDK9, providing a new strategy for exploring the comprehensive mechanism of the MOF-CDK9 axis in cellular processes.
- |||||||||| Review, Journal: CDK9 inhibitors for the treatment of solid tumors. (Pubmed Central) - Oct 26, 2024
In this review, we summarize the latest knowledge of CDK9 biology in solid tumors and the studies of small molecule CDK9 inhibitors. We discuss the results of the latest clinical trials of CDK9 inhibitors in solid tumors, with a focus on key issues to consider for improving the therapeutic impact of this drug class.
- |||||||||| Journal: Catch 'em all! CDK9's RUNX1 mega evolution. (Pubmed Central) - Oct 24, 2024
We discuss the results of the latest clinical trials of CDK9 inhibitors in solid tumors, with a focus on key issues to consider for improving the therapeutic impact of this drug class. No abstract available
- |||||||||| Journal: CDK9 phosphorylates RUNX1 to promote megakaryocytic fate in megakaryocytic-erythroid progenitors. (Pubmed Central) - Oct 24, 2024
While inhibition of known RUNX1 serine/threonine kinases does not affect phosphoserine RUNX1 levels in primary MEP, specific inhibition of CDK9 in MEP leads to both decreased RUNX1 phosphorylation and increased erythroid commitment. Collectively, our findings show that serine/threonine phosphorylation of RUNX1 promotes Mk fate specification and introduce a novel kinase for RUNX1 linking the fundamental transcriptional machinery with activation of a cell-type specific transcription factor.
- |||||||||| Journal: Herpes simplex virus 1 inhibits phosphorylation of RNA polymerase II CTD serine-7. (Pubmed Central) - Oct 22, 2024
Here, we demonstrate that viral proteins inhibit two key phosphorylation patterns on the C-terminal domain (CTD) of cellular RNA polymerase II and that this is separate from the degradation of polymerases later in infection. Furthermore, we show that viral genes do not require the full "CTD code." Together, these data distinguish multiple steps in the remodeling of RNA polymerase during infection and suggest that shared transcriptional phenotypes during stress responses do not revolve around a core disruption of CTD modifications.
- |||||||||| Journal: HEXIM1 homodimer binds two sites on 7SK RNA to release autoinhibition for P-TEFb inactivation. (Pubmed Central) - Oct 17, 2024
Here, we show that one Hexim1 homodimer binds two sites on linear 7SK RNA in a manner that exposes the Cdk9 binding sites, which are otherwise masked within the autoinhibited dimer. These results provide mechanistic insights into Hexim-RNA specificity and explain how P-TEFb can be effectively regulated to respond to changing levels of transcriptional signaling.
- |||||||||| THAL-SNS-032 - Dana / Farber Cancer Institute, Blenrep (belantamab mafodotin-blmf) / GSK
CDK9-dependent transcriptional regulation of BCMA in multiple myeloma: rational combination therapies (Singapore) - Oct 13, 2024 - Abstract #DGHO2024DGHO_653;
Having correlated CDK9 and BCMA expression in MM cells alone or in 2D- and 3D- coculture systems, the dependency of BCMA expression on CDK9 was demonstrated by genomic (transient siCDK9- and inducible Tet-on/shCDK-9-) approaches or by the proteolysis targeting chimera Thal-SNS-032 through selective degradation of CDK9. In summary, although therapeutic inhibition of CDK9 is a promising evolving option in MM therapy, its impact on strategies involving BCMA- targeting agents warrant further consideration for clinical application.
- |||||||||| Journal: Expression of CDK9 in Newly Diagnosed Patients with Acute Myeloid Leukemia and its Clinical Significance. (Pubmed Central) - Oct 9, 2024
In summary, although therapeutic inhibition of CDK9 is a promising evolving option in MM therapy, its impact on strategies involving BCMA- targeting agents warrant further consideration for clinical application. CDK9 is markedly upregulated in AML patients, suggesting its potential utility as both a prognostic indicator and a therapeutic target, particularly for patients with unfavorable clinical and pathological characteristics and poor prognosis.
- |||||||||| Journal: Relocalizing transcriptional kinases to activate apoptosis. (Pubmed Central) - Oct 3, 2024
Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.
- |||||||||| Review, Journal: Targeting Molecular Signaling Pathways and Cytokine Responses to Modulate c-MYC in Acute Myeloid Leukemia. (Pubmed Central) - Sep 30, 2024
Furthermore, we highlight Food and Drug Administration (FDA)-approved drugs for AML, and the results of preclinical and clinical studies on novel agents that have been or are currently being tested for efficacy and tolerability in AML therapy. Overall, this review summarizes our current knowledge of the molecular processes that promote leukemogenesis, as well as the various agents that intervene in specific pathways and directly or indirectly modulate c-MYC to disrupt AML pathogenesis and drug resistance.
- |||||||||| QHRD107 - Qianhong Bio / Pharma, SRA515 / GSK
Journal, IO biomarker: CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer. (Pubmed Central) - Sep 17, 2024
Overall, this review summarizes our current knowledge of the molecular processes that promote leukemogenesis, as well as the various agents that intervene in specific pathways and directly or indirectly modulate c-MYC to disrupt AML pathogenesis and drug resistance. Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
- |||||||||| Journal: Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability. (Pubmed Central) - Sep 12, 2024
Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.
- |||||||||| Journal: Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers. (Pubmed Central) - Sep 10, 2024
Moreover, modulating the tumor microenvironment (TME) by complement system intervention enhances the response to CDK9i and potently suppresses tumor growth. Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS-mutant patients.
- |||||||||| MM progression and evolution of refractory disease explained by integrative multiomics in Moffitt Cancer Center's patient cohort (101 B1-B2, Convention Center) - Sep 10, 2024 - Abstract #IMW2024IMW_186;
Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS-mutant patients. We demonstrate that MM progression and refractory disease are driven by a multifactorial dynamic, with multiple initiating genomic events causing genome-wide epigenetic and transcriptomic dysregulation.
- |||||||||| Journal: Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes. (Pubmed Central) - Sep 5, 2024
Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.
- |||||||||| Journal: Cocaine-induced DNA-PK relieves RNAP II pausing by promoting TRIM28 phosphorylation. (Pubmed Central) - Sep 4, 2024
These findings hold promise for the development of highly targeted therapeutics aimed at mitigating the detrimental effects of cocaine in individuals living with HIV. Cocaine upregulates both the expression and activity of DNA-PK.Cocaine augments the phosphorylation of DNA-PK selectively at S2056, a post-translational modification that marks functionally active form of DNA-PK.Cocaine enhances the nuclear translocation of DNA-PK.The DNA-PK inhibition severely impairs HIV transcription, replication, and latency reactivation.Cocaine facilitates the initiation and elongation phases of HIV by enhancing RNAPII CTD phosphorylation at Ser5 and Ser2, respectively, by stimulating DNA-PK.Cocaine also supports initiation and elongation phases of HIV transcription by stimulating CDK7 (the kinase of TFIIH) and CDK9 (the kinase subunit of P-TEFb), respectively.Cocaine-mediated activation of DNA-PK relieves RNAP II pausing by reversing the inhibitory effect of pausing factor TRIM28 and converting it into a transactivator by catalyzing its phosphorylation at S824 site.Thus, cocaine, by activating DNA-PK, facilitates the multiple phases of HIV transcription, namely, initiation, RNAP II pause-release, and elongation.
- |||||||||| Journal: Myrtleciclib, a CDK4/6/9 Inhibitor for the Treatment of Aggressive Cancers. (Pubmed Central) - Sep 3, 2024
Cocaine upregulates both the expression and activity of DNA-PK.Cocaine augments the phosphorylation of DNA-PK selectively at S2056, a post-translational modification that marks functionally active form of DNA-PK.Cocaine enhances the nuclear translocation of DNA-PK.The DNA-PK inhibition severely impairs HIV transcription, replication, and latency reactivation.Cocaine facilitates the initiation and elongation phases of HIV by enhancing RNAPII CTD phosphorylation at Ser5 and Ser2, respectively, by stimulating DNA-PK.Cocaine also supports initiation and elongation phases of HIV transcription by stimulating CDK7 (the kinase of TFIIH) and CDK9 (the kinase subunit of P-TEFb), respectively.Cocaine-mediated activation of DNA-PK relieves RNAP II pausing by reversing the inhibitory effect of pausing factor TRIM28 and converting it into a transactivator by catalyzing its phosphorylation at S824 site.Thus, cocaine, by activating DNA-PK, facilitates the multiple phases of HIV transcription, namely, initiation, RNAP II pause-release, and elongation. CDK4/6/9i might represent a new frontier in cancer treatment to overcome the limitations of CDK4/6i and CDK9i for the treatment of cancers, including aggressive cancers with high unmet needs.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Jakafi (ruxolitinib) / Incyte
Challenging Scenarios in the Management of Myeloproliferative Neoplasms () - Aug 30, 2024 - Abstract #SOHO2024SOHO_1029;
We envision that our imaging and analysis pipeline will be useful to reveal the organizational principles not only of the cell nucleus but also other cellular compartments. In particular, series looking at the use of venetoclax (VEN) based regimens have demonstrated median OS of 4-8 months33
- |||||||||| dinaciclib (MK-7965) / Merck (MSD)
INHIBITION OF CYCLIN-DEPENDENT KINASE 9 LEADS TO RAPID AND EFFECTIVE APOPTOSIS INDUCTION IN B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (311 Hall) - Aug 15, 2024 - Abstract #SIOP2024SIOP_460;
Interestingly, we identified strong activity of the pan-CDK inhibitor dinaciclib...We observed a dose-dependent reduction of RNA polymerase II (RNAP-II) activity and decreased expression of downstream pro-survival proteins c-MYC, BCL-XL and MCL-1, pointing to cell death induction via the inhibition of CDK9. In line with these observations, CDK9 inhibition with the specific inhibitor ADZ4573 also resulted in rapid apoptosis induction with caspase-3/7/8 activation and PARP cleavage, along with decreased RNAP-II phosphorylation and MCL-1 protein expression.Conclusions Taken together, we identified strong anti-leukemia activity by CDK9 inhibition characterized by rapid and effective cell death induction in BCP-ALL cell lines and PDX samples belonging to various different subtypes, warranting further pre-clinical evaluation.
- |||||||||| BTX-A51 / Edgewood Oncology
Journal: Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors. (Pubmed Central) - Aug 14, 2024
inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors...Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.
- |||||||||| Review, Journal: PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer. (Pubmed Central) - Aug 8, 2024
Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.
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