- |||||||||| Journal, IO biomarker: Advances on Epigenetic Drugs for Pediatric Brain Tumors. (Pubmed Central) - Sep 30, 2022
Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could be possibly used against the most common malignant tumors of childhood, such as medulloblastomas, high- grade gliomas and ependymomas.
- |||||||||| GFH009 / SELLAS Life Sciences
Clinical, PK/PD data, Preclinical, Journal: AML-259 Pharmacokinetics and Bioequivalence of Two Formulations of GFH009 Maleate Injection in Sprague Dawley Rats. (Pubmed Central) - Sep 29, 2022
In this review, we discuss recent progress on epigenetic drugs that could be possibly used against the most common malignant tumors of childhood, such as medulloblastomas, high- grade gliomas and ependymomas. The PK profiles of GFH009 were comparable following single IV administration of two formulations of GFH009 maleate injection in SD rats, which supported application of the pH 6.0 formulation in Phase I trials in patients with relapsed/refractory hematologic conditions, including AML and lymphoma.
- |||||||||| zotiraciclib (TG02) / Cothera Biosci
Targeting the selective vulnerability of IDH-mutant glioma with zotiraciclib (West/Central Hall) - Sep 28, 2022 - Abstract #SNO2022SNO_510;
Low-dose exposure of zotiraciclib induces cell death and suppresses transcriptional process and mitochondrial biogenesis in IDH-mutant glioma, not in IDH-wt tumors. These findings support a clinical trial testing zotiraciclib in IDH-mutated glioma.
- |||||||||| alvocidib (DSP-2033) / Sumitomo Pharma
Review, Journal: Chemical inhibitors of transcription-associated kinases. (Pubmed Central) - Sep 24, 2022
We then highlight the advantages of kinase inhibitors compared with other basic research methods, and describe the caveats associated with non-selective compounds (e.g. flavopiridol). We conclude with strategies and recommendations for implementation of chemical inhibitors for experimental analysis of transcription-associated kinases.
- |||||||||| Journal, PARP Biomarker: Ligand- and structure-based identification of novel CDK9 inhibitors for the potential treatment of leukemia. (Pubmed Central) - Sep 24, 2022
An online platform (called DEEPCDK9Pred) was developed based on the FP-GNN models to predict or design new CDK9 inhibitors. Collectively, our findings demonstrated that FP-GNN algorithm can achieve accurate prediction of CDK9 inhibitors and the subsequent discovery of C9 as a new potential CDK9 inhibitor deserves further structural modification for the treatment of leukemia.
- |||||||||| GFH009 / SELLAS Life Sciences
Pharmacokinetics and Bioequivalence of Two Formulations of GFH009 Maleate Injection in Sprague Dawley Rats () - Sep 22, 2022 - Abstract #SOHO2022SOHO_478;
Our study sheds light on the mechanisms of protein quality control under pathophysiological conditions. The PK profi les of GFH009 were comparable following single IV administration of two formulations of GFH009 maleate injection in SD rats, which supported application of the pH 6.0 formulation in Phase I trials in patients with relapsed/refractory hematologic conditions, including AML and lymphoma.
- |||||||||| Xospata (gilteritinib) / Astellas
Journal: Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor-mediated synergistic antileukemic actions. (Pubmed Central) - Sep 20, 2022
CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations.
- |||||||||| NMS-1116354 / Nerviano Medical Sciences
Journal: Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway. (Pubmed Central) - Aug 27, 2022
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: O-GlcNAc transferase maintains metabolic homeostasis in response to CDK9 inhibition. (Pubmed Central) - Aug 24, 2022
Our metabolite profiling data revealed that pantothenic acid (vitamin B5) is the metabolite that is most robustly induced by both OGT and OGT+CDK9 inhibitor treatments, but not by CDK9 inhibition alone. Finally, supplementing prostate cancer cell lines with vitamin B5 in the presence of CDK9 inhibitor mimics the effects of co-targeting OGT and CDK9.
- |||||||||| CDK9 Kinase Activation in Association with AFF1-SEC Initiate Epidermal Progenitor differentiation (Room 3) - Aug 16, 2022 - Abstract #ESDR2022ESDR_231;
Using co-immunoprecipitation, we further found that the interaction between AFF1 and HEXIM1 is specific to the progenitor state but not in differentiated keratinocytes. Thus, our data suggest that the activity switch of CDK9, in association with AFF1 and HEXIM1, underlies an early step of epidermal progenitor differentiation initiation, in rapid response to cellular signaling such as PKC activation
- |||||||||| Preclinical, Journal: Global phosphoproteomic analysis identified key kinases regulating male meiosis in mouse. (Pubmed Central) - Aug 13, 2022
Haspin knockout led to misalignment of chromosomes, apoptosis of metaphase spermatocytes and a decreased number of sperm by deregulation of H3T3ph, chromosomal passenger complex (CPC) and spindle assembly checkpoint (SAC). The complicated protein phosphorylation and its important regulatory functions in meiosis indicated that in-depth studies of phosphorylation-mediated signaling could help us elucidate the mechanisms of meiosis.
- |||||||||| chloroquine phosphate / Generic mfg., deferiprone / Generic mfg., doxorubicin hydrochloride / Generic mfg.
Journal: CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma. (Pubmed Central) - Aug 5, 2022
Additionally, because of the moderate and controlled inhibition of CDK9, OA not led to extreme repression of general transcription and appeared to overcome the inconsistent anti-HCC efficacy and high normal tissue toxicity that was associated with existing CDK9 inhibitors. All of the findings reveal that mitophagy disruption is a promising strategy for HCC treatment and OA is a potential candidate for the development of mitophagy inhibitors.Abbreviations: BNIP3: BCL2 interacting protein 3; CCCP: carbonyl cyanide p-trichloromethoxy-phenylhydrazone; CDK9: cyclin dependent kinase 9; CHX: cycloheximide; CQ, chloroquine; DFP: deferiprone; DOX: doxorubicin; EBSS: Earle's balanced salt solution; E64d: aloxistatin; FOXO3: forkhead box O3; HCC: hepatocellular carcinoma; HepG2/ADR: adriamycin-resistant HepG2 cells; MMP: mitochondrial membrane potential; mito-Keima: mitochondria-targeted and pH-sensitive fluorescent protein; MitoSOX: mitochondrial reactive oxygen species; OA: oroxylin A; PB: phosphate buffer; PDX: patient-derived tumor xenograft; PINK1: PTEN induced kinase 1; POLR2A: RNA polymerase II subunit A; p-POLR2A-S2: Ser2 phosphorylation of RNA polymerase II subunit A; PRKN: parkin RBR E3 ubiquitin protein ligase; SIRT1: sirtuin 1.
- |||||||||| Journal: KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM). (Pubmed Central) - Aug 3, 2022
Validation analysis on two independent MPM-patients sets, including a consecutive, retrospective cohort of 97 MPM, confirmed KAP1 as new non-genetic dependency of MPM and proved the association of its dependent gene program with reduced patients' survival probability. Overall these data: provided new insights into the biology of MPM delineating KAP1 and its target genes as building blocks of its clinical aggressiveness.
- |||||||||| Journal: Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells. (Pubmed Central) - Jul 29, 2022
Molecular docking showed that toyocamycin efficiently binds the CDK9 catalytic site in a conformation that differs from other CDKs, explained by the binding contribution of specific amino acids within the catalytic pocket and protein backbone. Altogether, we demonstrated that toyocamycin exhibits specific CDK9 inhibition in cancer cells, highlighting its potential for cancer chemotherapy.
- |||||||||| dinaciclib (MK-7965) / Ligand, Merck (MSD), seliciclib (CYC202) - Cyclacel, Cedars / Sinai
Journal: Purine analogues as potential CDK9 inhibitors: New pyrazolopyrimidines as anti-avian influenza virus. (Pubmed Central) - Jul 23, 2022
It was found that two sets of descriptors, 3 D Potential energy descriptors and 2 D Atom Counts and Bond Counts descriptors, were correlated to a linear model with RMSE and r2 coefficient values of 0.75 and 0.80, respectively. A molecular dynamic simulations study of 11f over 10 ns against dinaciclib showed that both 11f and dinaciclib achieved equilibrium at 2 Å.
- |||||||||| Zykadia (ceritinib) / Novartis, alvocidib (DSP-2033) / Sumitomo Dainippon, dinaciclib (MK-7965) / Ligand, Merck (MSD)
IDENTIFICATION OF NOVEL THERAPEUTICS FOR HEPATOBLASTOMA USING A PATIENT-DERIVED XENOGRAFT IN VITRO DRUG TESTING PLATFORM (Hall 7) - Jul 16, 2022 - Abstract #SIOP2022SIOP_480;
Most importantly, these drugs significantly reduced growth of a patient-derived xenograft model when transplanted into nude mice.ConclusionsWe were able to establish a platform for rapid, reproducible and reliable validation of potential drug candidates. Our results strongly suggest that ceritinib, dinaciclib, alvocidib, and mebendazole can be applied as an alternative therapeutic approach for hepatoblastoma.
- |||||||||| CDK7 and CDK9 Inhibition Induces RNA Polymerase II Ubiquitination and Proteasome Degradation in Thyroid Cancer Cells (ENDOExpo, Pod 12) - Jul 16, 2022 - Abstract #ENDO2022ENDO_2818;
We also identified a new mode of action for these drugs that may be important in selecting cancers for clinical trials. Learning Objective 1: CDK7 and CDK9 inhibitors are highly active against thyroid cancer cells Learning Objective 2: CDK7 and CDK9 inhibition result in RNA Polymerase II ubiquitination and proteasome degradation Science Topic(s) for Thryoid: Thyroid Neoplasia and Cancer (also see Tumor Biology)
- |||||||||| Review, Journal: CDK9 inhibitors in cancer research. (Pubmed Central) - Jul 12, 2022
This led to an intensive development of small-molecule CDK9 inhibitors or new emerging strategies, such as proteolysis targeting chimeras (PROTACs). Here, we review the CDK9 modulators in cancer not only for research purposes, but also for therapeutic applications.
- |||||||||| Journal: AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation. (Pubmed Central) - Jul 10, 2022
Interestingly, T527 as a phosphorylated residue has not been previously shown and sits in the transactivation domain, further implying a role for this site in HSF1 gene transactivation. This study suggests that HSF1 hyperphosphorylation is targeted and these specific residues have direct function in regulating HSF1 transcriptional activity.
- |||||||||| Review, Journal: Targeting cyclin-dependent kinase 9 in cancer therapy. (Pubmed Central) - Jul 8, 2022
Then, we provide an overview of some CDK9 inhibitors supported by multiple oncologic preclinical and clinical investigations. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.
- |||||||||| AT7519 / Novartis, Otsuka, seliciclib (CYC202) - Cyclacel, Cedars / Sinai
Journal: Inhibition of Cyclin-Dependent Kinase 9 Downregulates Cytokine Production Without Detrimentally Affecting Human Monocyte-Derived Macrophage Viability. (Pubmed Central) - Jun 14, 2022
Cyclin-dependent kinase (CDK) inhibitor drugs (CDKi), such as R-roscovitine and AT7519, induce neutrophil apoptosis in vitro and enhance the resolution of inflammation in a number of in vivo models...In addition, enhanced efferocytosis, induced by the glucocorticoid dexamethasone, was also unaffected after a short time treatment with R-roscovitine...Overall, this study demonstrates that pharmacological and genetic targeting of CDK9 inhibits an inflammatory phenotype in human MDMs. As such these data indicate that CDK9 may be key to therapeutically targeting pro-inflammatory macrophage functions during chronic inflammation.
- |||||||||| Herceptin (trastuzumab) / Roche, THAL-SNS-032 - Dana / Farber Cancer Institute
Journal: Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer. (Pubmed Central) - Jun 5, 2022
The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.
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