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- | Journal: TRIM24 controls induction of latent HIV-1 by stimulating transcriptional elongation. (Pubmed Central) - Jan 24, 2023
These results demonstrate a role of TRIM24 for regulation of transcriptional elongation from the HIV-1 promoter, through its interaction with TFII-I, and by recruitment of P-TEFb. Furthermore, these factors co-regulate a significant proportion of genes involved in T cell immune response, consistent with tight coupling of HIV-1 transcriptional activation and T cell signaling.
- | Journal: Design, synthesis and biological evaluation of 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives as CDK inhibitors. (Pubmed Central) - Jan 20, 2023
Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.
- ||||| Grant: Congratulations to Eddie Dominguez, a postdoctoral fellow in our lab who was awarded a prestigious LRF Grant to study CDK9 resistance in lymphoma. With Gratitude to @lymphoma for supporting young scientists careers (Twitter) - Jan 19, 2023
- | Journal: Discovery of Pongol, the Furanoflavonoid, as an Inhibitor of CDK7/Cyclin H/MAT1 and Its Preliminary Structure-Activity Relationship. (Pubmed Central) - Jan 17, 2023
The molecular docking and molecular dynamics simulation revealed that the presence of phenolic -OH in pongol is vital for kinase inhibition, as its absence resulted in a significant loss in activity (e.g., lanceolatin B). The prime MM-GBSA calculations revealed the presence of strong lipophilic and H-bonding interactions of pongol with CDKs.
- || topotecan / Generic mfg., irinotecan / Generic mfg.
Clinical data, Journal, IO biomarker, Machine learning: A machine learning framework develops a DNA replication stress model for predicting clinical outcomes and therapeutic vulnerability in primary prostate cancer. (Pubmed Central) - Jan 13, 2023
Additionally, RSS-high patients were more responsive to taxane-based chemotherapy and Poly (ADP-ribose) polymerase inhibitors, whereas RSS-low patients were more sensitive to androgen deprivation therapy. In conclusion, a robust machine-learning framework was used to reveal the great potential of RSS for personalized risk stratification and therapeutic implications in PCa.
- RNA Polymerase I inhibitors for cancer therapy () - Jan 13, 2023 - Abstract #LCC2023LCC_139;
We show that combinatorial therapy with CX-5461 and both Flavopiridol and Dinaciclib have a synergistic effect in vitro and significantly increase the survival of acute myeloid leukaemia (AML) models in vivo. Our data indicates that inhibition of both Pol I (by CX-5461) and Pol II (by CDK9 inhibitors) can be used in as a therapy to extend survival and reduce acquired resistance.
- || https://t.co/M0SVpCDK9X (Twitter) - Jan 12, 2023
- | ingenol mebutate / Generic mfg.
Journal: Inhibition of the TRIM24 bromodomain reactivates latent HIV-1. (Pubmed Central) - Jan 12, 2023
Notably, IACS-9571 did not cause global activation of T cells; rather, it inhibited induction of IL2 and CD69 expression in human PBMCs and Jurkat T cells treated with PEP005 or PMA. These observations indicate the TRIM24 bromodomain inhibitor IACS-9571 represents a novel HIV-1 latency reversing agent (LRA), and unlike other compounds with this activity, causes partial suppression of T cell activation while inducing expression of latent provirus.
- | Journal: Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors. (Pubmed Central) - Jan 9, 2023
Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.
- | Journal: The chaperone protein p32 stabilizes HIV-1 Tat and strengthens the p-TEFb/RNAPII/TAR complex promoting HIV transcription elongation. (Pubmed Central) - Dec 31, 2022
Likely due its scaffold properties, p32 also promoted Tat association with TAR, p-TEFb, and RNAPII enhancing Tat-dependent HIV transcription. In sum, we identified p32 as a host factor that interacts with and stabilizes Tat protein, promotes Tat-dependent transcriptional regulation, and may be explored for HIV-targeted transcriptional inhibition.
- | Journal: Distinct patterns of RNA polymerase II and transcriptional elongation characterize mammalian genome activation. (Pubmed Central) - Dec 29, 2022
Functional perturbations demonstrate that CDK9 and SPT5 are major ZGA regulators and that SPT5 prevents precocious activation of some genes. Overall, our work sheds molecular insights into transcriptional regulation at the beginning of mammalian development.
- | Journal: Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology. (Pubmed Central) - Dec 29, 2022
Pathway analysis of genetic co-dependency and drug sensitivity data show CDK7 and CDK9 have distinct relationships with major oncogenic signatures, including MYC and E2F targets, oxidative phosphorylation, and the unfolded protein response. Altogether, these results inform the improved design of therapeutic strategies targeting tCDKs in cancer.
- | Journal: Synthesis and biological activity evaluation of novel 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines. (Pubmed Central) - Dec 12, 2022
Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition. Further biochemical analyses and molecular docking confirmed FLT3 as a cellular target of 10b.
- | Venclexta (venetoclax) / Roche, AbbVie
Journal: Novel therapies and combinations in CLL refractory to BTK inhibitors and venetoclax. (Pubmed Central) - Dec 10, 2022
For young fit patients achieving remissions with salvage treatments, the option of allogeneic stem cell transplantation should be discussed as the outcome appears to be unaffected by number and type of previous targeted agents. Novel treatment strategies interfering with different mechanisms of CLL cell survival and proliferation are warranted, including small molecules with novel targets (eg, CDK9, MCL1, ERK inhibitors), CAR T cells targeting different antigens, CAR natural killer cells, or bispecific antibodies.
- JQ-1 / Roche
Targeting BRD4 potentiates YB-1 dependent oncolytic adenovirus XVir-N-31 through E1A12S-mediated redirection of cellular transcription machinery to viral genomes () - Nov 30, 2022 - Abstract #DKK2022DKK_2321;
Novel treatment strategies interfering with different mechanisms of CLL cell survival and proliferation are warranted, including small molecules with novel targets (eg, CDK9, MCL1, ERK inhibitors), CAR T cells targeting different antigens, CAR natural killer cells, or bispecific antibodies. Combining the oncolytic adenoviruses XVir-N-31 with BRD4 inhibition offers a novel approach to enhance the lytic effect of XVir-N-31 in a clinical setting.
- Delineating CDK9- Regulated Molecular Events for the Development of Rationally Derived Multiple Myeloma Treatment Strategies () - Nov 29, 2022 - Abstract #ASH2022ASH_7660;
Moreover, knockdown CDK9 by shRNA inhibited proliferation and survival, both in MM tumor cell- and tumor cell/BMSC co-cultures. Rationally derived combination strategies of Thal-sns-032 with venetoclax, navitoclax, Selinexor or Carfilzomib as well as other investigational and established MM therapies induced synergistic anti-MM effects in MM cells or BMSC co-cultures.Conclusion : In summary, by delineating CDK9-regulated molecular events in MM, our studies strongly support the therapeutic role of targeted CDK9-therapy and rationally derived MM combination treatment strategies.
- | Journal: Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy. (Pubmed Central) - Nov 27, 2022
Furthermore, low pCDK9 staining was significantly associated with superior RFS (p = 0.004) and DMFS (p = 0.001), and increased CSS (p = 0.022), and remained significant for these endpoints in the multivariate analyses. Increased caspase-8 and CDK9 levels correlate with improved disease-related outcomes in cervical cancer patients treated with CRT, whereas elevated pCDK9 levels predict worse survival in this patient population.
- | Journal: Design, synthesis and anticancer evaluation of selective 2,4-disubstituted pyrimidine CDK9 inhibitors. (Pubmed Central) - Nov 22, 2022
In vivo studies indicated that 8d exhibited potent anti-tumor effects in PANC-1 xenograft models without causing obvious loss of body weight. Our research suggests that compound 8d, as a potent CDK9 inhibitor, can be considered as a good lead-candidate for further development.
- | Journal: Identification of a novel CDK9 inhibitor targeting the intramolecular hidden cavity of CDK9 induced by Tat binding. (Pubmed Central) - Nov 22, 2022
We inspected the amino acid sequence and structural properties of the CDK9 hidden cavity to determine whether it is conserved in other CDKs, such as CDK6. The Ile61, comprising the center of the CDK9 hidden cavity, appears to be crucial for its kinase activity, thus indicating that the identification of the CDK9 hidden cavity may provide vital information for the development of novel CDK9 inhibitors.
- | Journal: Discovery of Novel and Potent Inhibitors of Cyclin-Dependent Kinases 7 and 9: Design, Synthesis, Structure-Activity Relationship Analysis and Biological Evaluation. (Pubmed Central) - Nov 20, 2022
Among them, N-(6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl)-4-(imidazo[1,2-a]pyrimidin-3-yl)pyrimidin-2-amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti-proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4-11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub-G1 phase and induced apoptosis.
- | Journal: Castration-resistant prostate cancer cells are dependent on the high activity of CDK7. (Pubmed Central) - Nov 20, 2022
The cellular mode of action of this compound was investigated in MV4-11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub-G1 phase and induced apoptosis. We show that CRPC cells, but not normal prostate cells, are addicted on the high activity of the key transcriptional kinases, CDK7 and CDK9.
- | enitociclib (VIP152) / Vincerx
Journal: The non-apoptotic function of Caspase-8 in negatively regulating the CDK9-mediated Ser2 phosphorylation of RNA polymerase II in cervical cancer. (Pubmed Central) - Nov 19, 2022
Combining BAY1251152 with Cisplatin synergistically overcame chemoresistance of Caspase-8-deficient cervical cancer cells. Therefore, Caspase-8 expression could be a marker in chemoresistant cervical tumors, suggesting CDK9 inhibitor treatment for their sensitization to Cisplatin-based chemotherapy.
- | enitociclib (VIP152) / Vincerx
Preclinical, Journal: VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia. (Pubmed Central) - Nov 17, 2022
Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
- ||| AZD4573 / AstraZeneca
Novel BCL-2 downstream signalling inhibitors and combinations to be presented at #ASH22 🧵 https://t.co/Sz6HZDuIt5 #ASH22 AZD4573 is a highly potent and selective CDK9 inhibitor that rapidly and preferentially decreases BCL2 family anti-apoptotic & MYC. Phase 1 study (Twitter) - Nov 9, 2022
- | Journal: Computational Investigations of Coumarin Derivatives as Cyclin-Dependent Kinase 9 Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation. (Pubmed Central) - Nov 8, 2022
These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL. The thesis has argued that a valuable insight for further research on novel and effective inhibitors targeting CDK9 has been provided.
- | Journal: Medicinal Chemistry of Pyrazolopyrimidine Scaffolds Substituted with Different Heterocyclic Nuclei. (Pubmed Central) - Nov 5, 2022
This review provides an overview of the different pharmacological activities of the pyrazolopyrimidine scaffold and its correlation with chemical structure. Some exciting new developments in pyrazolopyrimidine scaffolds are also presented in this review.
- Venclexta (venetoclax) / Roche, AbbVie, enitociclib (VIP152) / Vincerx
Preclinical Study of Enitociclib, a Selective CDK9 Inhibitor, in Combination with Bortezomib, Lenalidomide, Pomalidomide, or Venetoclax in the Treatment of Multiple Myeloma (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_6632;
Our studies present the first proof-of-concept evidence that enitociclib has significant antitumor activity against several MM cell lines and provides specific pharmacological targetability of several key oncogenic pathways involving proteins such as MYC, MCL1 and PCNA, leading to growth inhibition and apoptosis. Taken together, the data provide the rationale and biological reasoning for further optimization studies of CDK9 inhibitors for clinical application to improve MM patient outcomes.
- Venclexta (venetoclax) / Roche, AbbVie
First in Human (FIH) Study of GFH009, a Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, in Patients with Relapsed/Refractory (r/r) Hematologic Malignancies (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_6079;
P1
The dose escalation in patients with AML and lymphoma is ongoing. Different dosing regimens are currently being explored for potentially better inhibition on the target.
- enitociclib (VIP152) / Vincerx
Enitociclib (VIP152/formerly BAY1251152) Is a Selective and Active CDK9 Inhibitor : Preliminary Safety and Early Signs of Efficacy in Patients with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_6072;
P1
Enitociclib has a favorable safety profile with evidence of clinical activity in DH-DLBCL and perhaps, with longer follow up, in other B-cell malignancies. Also, we show that enitociclib downregulates the MYC transcriptional program and is unlikely to abrogate vaccine efficacy, an important feature given the current COVID-19 pandemic.
- Anagrelide Represents a Potential Therapeutic Therapy for Acute Myeloid Leukemia Cells Based on Phosphodiesterase 3A Expression (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5735;
In conclusion, our clinical data suggested that high expression of PDE3A in newly diagnosed pediatric AML patients was associated with poor clinical survival. Besides, our in vitro and in vivo data indicated that ANA targeting PDE3A suppressed progression of AML by interrupting cell cycle, providing a promising approach to eradicate AML with high level of PDE3A expression.
- GFH009 / SELLAS Life Sciences
In Vitro and In Vivo Studies Support GFH009, a Selective CDK9 Inhibitor, As a Potential Treatment for Hematologic Cancers (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4867;
GFH009 is a potent and highly selective CDK9 inhibitor with the ability to reduce expression of downstream oncogenes required for rapid cellular division and protein expression through specific, short-lived inhibition of CDK9. We postulate that this mechanism drives GFH009’s inhibition of cellular division, as tumor stabilization and shrinkage appear to be dose-dependent.
- zelavespib intravenous (PU-H71 IV) / Samus Therap, Tecartus (brexucabtagene autoleucel) / Gilead, AZD4573 / AstraZeneca
Targeting the HSP90-MYC-CDK9 Axis to Overcome Dual Resistance to BTK Inhibition and CAR-T Therapy in Mantle Cell Lymphoma (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2376;
Targeting HSP90 with two independent inhibitors PU-H71 or 17-AAG was also potent in MCL preclinical models...Conclusion Our data demonstrated that an unexpected but novel axis led by HSP90-MYC-CDK9 drives the dual resistance to BTKi and CAR T therapies. Our study sheds light on the underlying mechanism of CAR-T resistance in addition to BTKi resistance in MCL and provides compelling preclinical evidence for therapeutic targeting of the HSP90-MYC-CDK9 axis to overcome the dual resistance in patients with MCL.
- AZD4573 / AstraZeneca
Safety, Tolerability, Pharmacokinetics (PK) and Preliminary Antitumor Activity of the Cyclin-Dependent Kinase-9 (CDK9) Inhibitor AZD4573 in Relapsed/Refractory Hematological Malignancies: A Phase 1 First-in-Human Study (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2187;
P1, P1/2
The reduction in pSer2 and MCL-1 supports the RP2D of 12 mg for lymphoma and 9 mg for leukemia. A combination study of AZD4573 and acalabrutinib (NCT04630756) is ongoing to further examine the DLBCL response signal seen in this study.
- PLX51107 / Daiichi Sankyo, dinaciclib (MK-7965) / Ligand, Merck (MSD)
The Multi-CDK Inhibitor Dinaciclib Shows Synergistic Activity with the BET Inhibitor PLX51107 and Reverses BET Resistance through Inhibition of Canonical Wnt Signaling in Acute Myeloid Leukemia (AML) (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2159;
We also found decreased disease burden by bioluminescence and by histopathology in combination treated animals, compared to both vehicle and single agent controls. In conclusion, we have demonstrated in vitro and in vivo synergistic activity of the BET inhibitor PLX51107 in combination with dinaciclib in pre-clinical models of AML and have identified novel inhibition of Wnt / ß-catenin signaling by dinaciclib, thereby providing a strategy to circumvent resistance to BET inhibitors in AML.
- Multiple Myeloma Evolution Is Characterized By Dynamic Epigenetic Landscapes (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2138;
In conclusion, MM progression, characterized by transcriptional dysregulation in response to TME and therapeutic stress, is epigenetically driven by DBPs whose activity is altered by genetic, cytogenetic, and epigenetic events. Future studies will determine the role of such master regulators in MM biology and drug resistance, as well as allow us to propose patient-specific strategies for therapy re-sensitization.
- HEXIM1 Overexpression Alters GATA1 Activity and Promotes Fetal Globin Expression (ENMCC - 391-392) - Nov 4, 2022 - Abstract #ASH2022ASH_1702;
Novel RNPII and GATA1 peaks were also identified in other genes associated with a fetal erythroid phenotype, most notably ARID3A and LIN28B. Together, these results support a model where elevated HEXIM1 levels promote the pioneer activity of GATA1, and facilitate the expression of a fetal transcriptional program in adult cells in a pTEFb-dependent manner.
- Xospata (gilteritinib) / Astellas
Genome-Wide CRISPR/Cas9 Knockout Screen Reveals Novel Gilteritinib Combinations Targeting Oxidative Phosphorylation and De-Novo Purine Biosynthesis Pathways for FLT3-ITD+ Acute Myeloid Leukemia (ENMCC - 353-355) - Nov 4, 2022 - Abstract #ASH2022ASH_1679;
Our data showcase a novel convergence of oxidative phosphorylation and nucleotide synthesis on the FLT3 axis in FLT3-ITD+ AML. We believe that our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations.
- PRT2527 / Prelude Therap
PRT2527, a Novel Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, Has Potent Anti-Leukemic Activity in Preclinical Primary Models of Human B-ALL, T-ALL, and CLL (ENMCC - 388-390) - Nov 4, 2022 - Abstract #ASH2022ASH_1609;
Doxorubicin, Ibrutinib and Venetoclax served as positive control therapeutic agents to assess the responsiveness of primary cultures ex vivo...Notably, the two less responsive models were from CLL patients who responded to Rituximab/Ibrutinib SoC therapy without further disease progression...These data and those reported previously support the advancement of PRT2527 into clinical studies in leukemia patients, especially in patients refractory or progressing on standard therapies. PRT2527 is currently in phase 1 studies in solid tumor patients.
- Disrupting MGA-MYC Driven Metabolic Reprogramming in Richter's Syndrome Pre-Clinical Models Via Novel Therapeutic Approaches (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_6244;
In summary, our murine model reveals that MGA/MYC/NME1 axis drives RS through increased mitochondrial OXPHOS and ROS accumulation. Moreover, targeting this axis provides therapeutic benefits for RS, highlighting this pathway as a novel potential target for RS treatment.
- Calquence (acalabrutinib) / AstraZeneca, AZD4573 / AstraZeneca
Phase 1b/2a Study of AZD4573 (CDK9i) and Acalabrutinib in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL): Results from Dose-Escalation (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4344;
P1, P1/2
No DLTs were detected, the combination was well tolerated with a manageable safety profile, and no new safety signals were identified. The study is currently enrolling in the Phase 2a expansion phase and updated data will be presented at the meeting.
- | Journal, PARP Biomarker, IO biomarker: LS-007 inhibits melanoma growth via inducing apoptosis and cell cycle arrest and regulating macrophage polarization. (Pubmed Central) - Nov 3, 2022
In addition, LS-007 induced higher apoptotic rate of B16F10 cells when co-cultured B16F10 with BMDMs. LS-007 has inhibitory effects on B16F10 cells in vivo and in vitro via inducing apoptosis, cell cycle arrest, and changing macrophage function in the TME.
- | Preclinical, Journal: 3,4,3'-Tri-O-methylellagic acid as an anticancer agent: in vitro and in silico studies. (Pubmed Central) - Nov 3, 2022
T-EA showed a binding free energy towards the SIRT1 protein of ΔG : -30.98 ± 0.25 kcal mol and ΔG : -24.07 ± 0.30 kcal mol, while that of CDK9 was ΔG : -29.50 ± 0.22 kcal mol and ΔG : -25.87 ± 0.40 kcal mol. The obtained results from this research could be considered as important information on 3,4,3'-tri-O-methylellagic acid as a drug to treat cervical and breast cancers.
- | pomalidomide / Generic mfg.
Journal: Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC). (Pubmed Central) - Nov 2, 2022
Based on previously developed competitive inhibitor of FLT3 and CDK9, we have designed and prepared a novel pomalidomide-based PROTAC...Moreover, transcriptional repression caused by CDK9 degradation significantly reduced expression of crucial genes involved in AML pathogenesis. The obtained results indicate the beneficial impact of simultaneous FLT3-ITD/CDK9 degradation for AML therapy.
- | SNS-032 / Viracta Therap
Journal, PARP Biomarker, IO biomarker: SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9. (Pubmed Central) - Nov 1, 2022
In active HSCs with CDK9 knockdown, the expression levels of CDK9, phosphorylated RNA polymerase II, XIAP, Bcl-2, Mcl-1, and ɑ-SMA significantly decreased, whereas those of cleaved-PARP1 and Bax decreased prominently. These results indicated that SNS-032 is a potential drug and CDK9 might be a new prospective target for the treatment of liver fibrosis.
- | Biomarker, Journal, PARP Biomarker: Targeting the ALK-CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex. (Pubmed Central) - Oct 26, 2022
Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK-p-Tyr19-CDK9 expression.
- | Journal: Comprehensive proteomic analysis reveals dynamic phospho-profiling in human early erythropoiesis. (Pubmed Central) - Oct 22, 2022
Collectively, our phosphoproteomic profiling, integrative network analysis and functional studies define landscapes of the phosphoproteome and reveal signalling pathways that are involved in human early erythropoiesis. This study will serve as a valuable resource for further investigations of phosphatase and kinase functions in human erythropoiesis and erythroid-related diseases.
- | AZD4573 / AstraZeneca
Journal: Proteomics and phosphoproteomics of chordoma biopsies reveal alterations in multiple pathways and aberrant kinases activities. (Pubmed Central) - Oct 18, 2022
We additionally examined 208 proteins whose expression and phosphorylation levels were synergetically altered. We herein depicted the collective protein profiles of chordomas, providing insight into chordomagenesis and the potential development of new therapeutic targets.
- | Journal: CDK9 and PP2A regulate RNA polymerase II transcription termination and coupled RNA maturation. (Pubmed Central) - Oct 12, 2022
We also confirm the splicing factor SF3B1 as a target of CDK9 and show that SF3B1 in complex with polyadenylation factors is lost from chromatin after CDK9 inhibition. These results emphasize the important roles that CDK9 plays in coupling transcription elongation and termination to RNA maturation downstream of the EEC.
- | Biomarker, Journal: Epigenetic oncogenesis, biomarkers and emerging chemotherapeutics for breast cancer. (Pubmed Central) - Oct 12, 2022
The review presents a model for a wider understanding of epigenetic oncogenic pathways to BC and reveals plausible channels for reversing the unpleasant changes through epigenetic modifications. It advances the science of therapeutic designs for ameliorating the global burden of BC for further translational studies.
- Effect of HIV-1 subtype C transactivator of transcription (Tat) P21A variant on nuclear levels of active positive transcription elongation factor b (P-TEFb), TAR binding and disease outcome (Virtual) - Oct 4, 2022 - Abstract #HIVGlasgow2022HIV_Glasgow_351;
Interestingly, TatP21 is able to bind TAR more efficiently than TatA21 thus revealing a possible mechanism but which the reduced functionality in SDMs and in patients was observed. Further investigation is required to determine whether these Tat variants play a role in latency development or reversal.