- |||||||||| Journal: P-TEFb is degraded by Siah1/2 in quiescent cells. (Pubmed Central) - May 26, 2022
Importantly, the inhibition of Siah1/2 rescued the expression of free CycT1 in proliferating as well as resting primary cells. We conclude that Siah1/2 are the E3 ligases that bind and degrade the dissociated CycT1 in resting, terminally differentiated, anergic and/or exhausted cells.
- |||||||||| tamoxifen / Generic mfg.
ROLE OF CDK9 AS A PROMISING THERAPEUTIC TARGET IN ER POSITIVE BREAST CANCER CELLS (RM 4(Walker Hall 2)) - May 16, 2022 - Abstract #GBCC2022GBCC_266;
Inhibition of CDK9 synergistically effects the endocrine therapy of ER+ breast cancers. Therefore, we suggest that the possibility that CDK9 could be a novel therapeutic target that can help the effective treatment of ER+ breast cancers.
- |||||||||| Journal: Measuring the precise position of transitions in transcription with PRO-IP-seq. (Pubmed Central) - May 14, 2022
Initial PRO-IP-seq (Precision Run-on Immunoprecipitation sequencing) data shows that we can enrich for populations of Pol II bound by specific transcription factors. Utilizing this tool, we will be able to measure genomically where both stable and more transient transcription factors interact with Pol II at near single-base resolution.
- |||||||||| VIP152 / Vincerx
VIP152 IS A NOVEL CDK9 INHIBITOR WITH IMPROVED SELECTIVITY, TARGET MODULATION, AND CARDIAC SAFETY IN PATIENTS WITH LYMPHOMA () - May 13, 2022 - Abstract #EHA2022EHA_1705;
P1
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.
- |||||||||| AT7519 / Novartis, Otsuka
Journal: AT7519 against lung cancer via the IL6/STAT3 signaling pathway. (Pubmed Central) - May 12, 2022
Taken together, AT519 exhibits great anti-tumor effects in lung cancer, and the mechanism was related closely to IL-6/STAT3 signaling pathway, which suggests the important roles of STAT3 in CDKs inhibitors. AT7519 might be a novel potential therapeutic agent based on this rationale.
- |||||||||| Journal: Phosphorylated MED1 links transcription recycling and cancer growth. (Pubmed Central) - May 10, 2022
Importantly, MED1 phosphorylation increases during prostate cancer progression to the lethal phase, and pharmacological inhibition of CDK9 decreases prostate tumor growth by decreasing MED1 phosphorylation and Pol II recycling. Our results reveal a novel role of MED1 in Pol II transcription and identify phosphorylated MED1 as a targetable driver of dysregulated Pol II recycling in cancer.
- |||||||||| Journal: Functional characterization of the human Cdk10/Cyclin Q complex. (Pubmed Central) - May 6, 2022
We also identify Cdk10 as an in vitro substrate of Cdk1 and Cdk5 at multiple sites, allowing for a potential cross-talk between these CDKs. With this functional characterization, Cdk10 adopts a hybrid position in both cell cycle and transcriptional regulation.
- |||||||||| MI-503 / Kura Oncology
Menin inhibitors as targeted therapeutics in KMT2a rearranged infant leukemia and the identification of effective treatment combinations. (Available On Demand; 239) - Apr 28, 2022 - Abstract #ASCO2022ASCO_3792;
In this study, we present and discuss the initial proof-of-concept preclinical data for the effective anti-leukemic activity of menin inhibition against KMT2A-rearranged infant leukemia cells. Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), dinaciclib (MK-7965) / Ligand, Merck (MSD)
Clinical, P1 data, Journal: Pembrolizumab plus dinaciclib in patients with hematologic malignancies: the phase 1b KEYNOTE-155 study. (Pubmed Central) - Apr 27, 2022
P1
These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti-PD-1 and CDK9 inhibitor combinations is warranted. Clinical trial registration: ClinicalTrials.gov, NCT02684617.
- |||||||||| Review, Journal, IO biomarker: Clinical considerations for the design of PROTACs in cancer. (Pubmed Central) - Apr 23, 2022
MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.
- |||||||||| cytarabine / Generic mfg.
CO-TARGETTING CDK9 AND BCL-2 TO COMBAT CYTARABINE RESISTANT ACUTE MYELOID LEUKEMIA () - Apr 20, 2022 - Abstract #ASPHO2022ASPHO_137;
Our results demonstrate promising antileukemic activity of the combination of AZD4573 and Venetoclax against AraC-resistant AML cells. Future studies will determine the in vivo efficacy of this promising combination therapy against AraC-resistant xenograft NSGS mouse models.
- |||||||||| Journal: Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex. (Pubmed Central) - Apr 20, 2022
In addition, we find that inhibition of DDX21 suppresses RNAa by miR-34a and other miRNAs without inhibiting post-transcriptional regulation. Our findings reveal a strong connection between RNAa and release of paused Pol II, facilitating RNAa research by making it possible to separately analyze post-transcriptional regulation and RNAa.
- |||||||||| alvocidib (DSP-2033) / Sumitomo Dainippon, dinaciclib (MK-7965) / Ligand, Merck (MSD)
Journal: Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors. (Pubmed Central) - Apr 13, 2022
Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options...Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531...Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, PIK-75 / VetDC
Journal, IO biomarker: PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma. (Pubmed Central) - Apr 13, 2022
Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance.
- |||||||||| Journal: Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations. (Pubmed Central) - Apr 9, 2022
Here, we substantiate these findings with the following (i) true drug synergy was exhibited by various chemical classes of PKI pairs directed to pUL97 and CDK7; (ii) no putative amplification of cytotoxicity by these drug combinations was observed; (iii) a reduction in drug dosage levels for synergistic combinations was defined on a quantitative basis and compared to monotreatments; (iv) the quantities of target proteins CDK7 and pUL97 expressed in HCMV-infected cells were assessed by confocal imaging, indicating a strong down-modulation of CDK7 levels as a result of synergistic drug treatment; (v) the functional importance of these target kinases, both binding to cyclin H, was illustrated by assessing HCMV replication under the viral genomic deletion of ORF-UL97 or cellular cyclin knock-out; (vi) new combinations of HCMV-specific drug synergy were demonstrated for solely host-directed treatments using PKIs against CDK2, CDK7, CDK8 and/or CDK9 and (vii) a triple PKI combination provided further support for the synergy approach. With these combined findings, this study highlights the potential of therapeutic drug combinations of approved, developmental and preclinical PKIs for expanding future options for anti-HCMV therapy.
- |||||||||| AT7519 / Novartis, Otsuka
Clinical, Journal: Global Phosphoproteomics reveal CDK suppression as a vulnerability to KRAS addiction in Pancreatic Cancer. (Pubmed Central) - Apr 1, 2022
In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline. A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically-exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in pancreatic cancer patients.
- |||||||||| Journal: Synthesis of 4-styrylpyrazoles and evaluation of their inhibitory effects on cyclin-dependent kinases. (Pubmed Central) - Apr 1, 2022
A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically-exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in pancreatic cancer patients. The prepared styrylpyrazoles showed inhibition activity towards CDKs and can provide a novel chemotype of kinase inhibitors.
- |||||||||| Biomarker, Journal: The Prognostic Role of CDK9 in Bladder Cancer. (Pubmed Central) - Mar 26, 2022
High CDK9 expression predicts a favorable prognosis in urothelial carcinoma and is associated with clinicopathological features characteristic for early-stage disease. The decrease in CDK9 expression can be associated with the build-up of genetic instability and may indicate a key role for CDK9 in the early stages of urothelial carcinoma.
- |||||||||| lenalidomide / Generic mfg.
Review, Journal: CDK9 inhibitors in multiple myeloma: a review of progress and perspectives. (Pubmed Central) - Mar 23, 2022
Synergistic effects between CDK9 inhibitors and either Venetoclax, Bortezomib, Lenalidomide or Erlotinib have been proven and are awaiting verification in clinical trials. Although conclusions should be drawn with due care, obtained reports suggest that including CDK9 inhibitors into the current drug regimen may turn out to be beneficial, especially in poor prognosis patients.
- |||||||||| Journal: Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma. (Pubmed Central) - Mar 15, 2022
Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself, by supporting TFIIH (CDK7)- and P-TEFb (CDK9)-mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in MM functioning through regulation of MYC-target gene transcription, and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells. (Pubmed Central) - Mar 15, 2022
Genetic or pharmacological targeting of YY1-CDK9 complex elicited RNA m6A modification-dependent interferon responses, reduced regulatory T cell infiltration, and augmented efficacy of immune checkpoint therapy in glioblastoma. Collectively, these results suggest that YY1-CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in glioblastoma.
- |||||||||| Clinical, Journal: Inhibition of CDK9 activity compromises global splicing in prostate cancer cells. (Pubmed Central) - Mar 11, 2022
Finally, we demonstrate that CDK9 expression increases as PC cells develop CRPC-phenotype both in vitro and also in patient samples. To conclude, here we show that CDK9 inhibition compromises splicing in PC cells, which can be capitalized on by targeting the PC-specific addiction androgen receptor.
- |||||||||| VIP152 / Vincerx
YK-2168, a potent and selective small molecule CDK9 inhibitor (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_7276;
These results together with GLP safety results are considered highly promising and warrant moving the compound forward to clinical investigation. In fact, YK-2168 was granted phase I clinical trials in both US and China.
- |||||||||| Discovery and preclinical evaluation of a novel highly selective and potent CDK12 inhibitor (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6944;
Besides the efficacy as a single reagent, the efficacy was augmented when CRD-1835439 was combined with PARP inhibitors in in vitro and in vivo.In summary, the novel small-molecule CDK12 inhibitor CRD-1835439 demonstrated preclinical efficacy along with target engagement. Our results underscore the preclinical therapeutic potential of CRD-1835439 as a single-agent or in combination with PARP inhibitors for the treatment of intractable cancers.
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