- |||||||||| JQ-1 / Roche, birabresib (OTX015) / Merck (MSD)
The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies (W311EFGH, Level 3 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5190;
SPI1 knockdown significantly reduced the resistance to OTX015 of AML cells whose MTHFR expression was suppressed or MLL-AF9-transformed Mthfr knockout primary murine cells . Our data provide a rationale for screening MTHFR polymorphisms and the folate cycle status to exclude patients least likely and nominate those most likely to benefit from MYC-targeting therapies.
- |||||||||| Thalomid (thalidomide) / Fujimoto, BMS, SNS-032 / Sunesis
Functional Characterization of E3 Ligases and Their Regulators: Therapeutic Implications for Development of New Proteolysis-Targeting Chimeric Degraders of Oncoproteins (Hall E2, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_1706;
The discovery that thalidomide derivatives recruit the E3 ligase CRBN to induce neomorphic degradation of proteins critical for multiple myeloma (MM) cells stimulated the research into proteolysis-targeting chimeric compounds (PROTACs), led to development of several CRBN- or VHL-based PROTACs against various oncoproteins and put a new spotlight on the biology and therapeutic targeting of E3 ligases in human neoplasias...We thus performed genome-scale CRISPR-based gene editing (for loss-of-function, LOF) studies in MM.1S cells treated with PROTACs targeting BET bromodomain proteins through MDM2 (A1874), CRBN (dBET6) or VHL (ARV-771 or MZ-1) or targeting CDK9 through CRBN (Thal-SNS-032); and validated key hits with individual sgRNAs in different MM cell lines...KCMF1, RNF4) which, to our knowledge, have not been leveraged for design of PROTACs, but warrant consideration given their patterns of essentiality in “high expressor” tumor cells . Our study provides insights on differential regulation and distinct patterns of essentiality for different E3 ligases and informs the design of new PROTACs which leverage different E3 ligases to help delay/overcome treatment resistance in MM and beyond.
- |||||||||| Journal: CDK9 and mTOR: trading places. (Pubmed Central) - Oct 29, 2019
Therefore, CDK9 may represent a promising target for the treatment of synovial sarcomas. No abstract available
- |||||||||| Journal: Cereblon as a primary target of IMiDs (Pubmed Central) - Oct 28, 2019
Various derivatives of thalidomide, a drug that is well-known for its teratogenicity, have recently been developed; among them, lenalidomide and pomalidomide, known as immunomodulatory drugs (IMiDs), have potent anticancer activity...Currently, researchers are investigating CC-122 (avadomide) and CC-220 (iberdomide) for the treatment of diffuse large B-cell lymphoma and systemic lupus erythematosus, respectively...Moreover, several proteins, such as BRD4, CDK9, or Tau, have already been successfully degraded by CRBN-based PROTACs. In this review, recent advances in CRBN and its binding compounds have been discussed.
- |||||||||| Journal, IO Biomarker: New therapeutic agents for acute myeloid leukemia (Pubmed Central) - Oct 28, 2019
Moreover, clinical trials of alvocidib (flavopiridol), an inhibitor of the CDK9, pevonedistat, an inhibitor of NEDD8, and APR-246, a reactivator of mutant p53, are in progress. These agents will either be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents to improve the outcome of AML therapy, and the results will guide the next stage of precision medicine in the treatment of AML.
- |||||||||| NMS-1116354 / Nerviano Medical Sciences
Journal, IO Biomarker: Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML. (Pubmed Central) - Oct 20, 2019
Importantly, the CD34/CD38 leukemic stem cell-encompassing population was equally sensitive to the combination of PHA-767491 and ABT-737. These results indicate that Bcl-2/Bcl-X and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival.
- |||||||||| Journal: MALAT1 induces osteosarcoma progression by targeting miR-206/CDK9 axis. (Pubmed Central) - Oct 8, 2019
Besides these, CDK9 was predicted as a downstream gene of miR-206, and we observed that MALAT1 can regulate osteosarcoma progress by modulating CDK9 expression via sponging miR-206. In conclusion, our study implied that MALAT1/miR-206/CDK9 axis can provide novel insights into the biological mechanism of osteosarcoma progression.
- |||||||||| Clinical, Journal: SUMO suppresses and MYC amplifies transcription globally by regulating CDK9 sumoylation. (Pubmed Central) - Oct 2, 2019
Transcription profiling analyses reveal that SUMO represses global transcription, particularly of moderately to highly expressed genes and by generating a sumoylation-resistant CDK9 mutant, we confirm that sumoylation of CDK9 inhibits global transcription. Together, our data reveal that SUMO and MYC oppositely control global gene expression by regulating the dynamic sumoylation and desumoylation of CDK9.
- |||||||||| Ibrance (palbociclib) / Pfizer, Verzenio (abemaciclib) / Eli Lilly
Differential mechanisms of acquired resistance to Abemaciclib versus Palbociclib reveal novel therapeutic strategies for CDK4/6 therapy-resistant breast cancers (Stars at Night Ballroom 1&2 - 3rd Level) - Sep 25, 2019 - Abstract #SABCS2019SABCS_1210;
Western blot analysis revealed a dose dependent downregulation of ERα, Rb, p-Rb and p27, while levels of cyclin E and p-CDK2 increased in a stepwise fashion in palbociclib resistant cells, which were only partially cross resistant to abemaciclib and sensitive to CDK9 inhibitors LDC067 and SNS032... Our results suggest that mechanisms underlaying palbociclib and abemaciclib acquired resistance exhibit differentially altered pathways, such as DNA damage/repair pathways, which can be exploited to overcome CDK4/6 inhibitors therapy resistance in breast cancer patients.
- |||||||||| Targeting CDK9 and MCL1 in castration-sensitive and resistant prostate cancer models (Board 81: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_513;
TP-1287 treatment (1.25 mpk BID) in combination with 100 mpk venetoclax demonstrated 64% tumor growth inhibition in the 22Rv1 CRPC model that was resistant to docetaxel, enzalutamide and venetoclax alone. These data support the potential of TP-1287 to be used in combination with currently available or novel therapies to achieve better efficacy for androgen sensitive and CRPC patients.
- |||||||||| zotiraciclib (TG02) / Adastra Pharma
Clinical, Journal: Novel Targeting of Transcription and Metabolism in Glioblastoma. (Pubmed Central) - Sep 14, 2019
These data support the potential of TP-1287 to be used in combination with currently available or novel therapies to achieve better efficacy for androgen sensitive and CRPC patients. TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial.
- |||||||||| Journal, PD(L)-1 Biomarker, IO biomarker: Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. (Pubmed Central) - Aug 30, 2019
By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
- |||||||||| Journal: Characterization of Toxoplasma gondii Spt5 like transcription elongation factor. (Pubmed Central) - Aug 11, 2019
TgSpt5 along with TgSpt4 could successfully complement the loss of function mutations in yeast counterparts emphasizing its functional significance. Together, the results highlight the possible role of TgSpt5 in transcript elongation regulated through phosphorylation by TgCrk9.
- |||||||||| Clinical, Journal: Visualization of global RNA synthesis in a human (mini-) organ in situ by click chemistry. (Pubmed Central) - Aug 1, 2019
By treating human HFs with the cytotoxic cell cycle inhibitor (R)-CR8, which inhibits transcriptional regulators CDK7 and CDK9, it was further shown that this technique can be used to sensitively detect changes in global RNA synthesis in situ. Together, this work delineates new insights into nascent RNA synthesis within a human (mini)- organ and describes a novel read-out parameter that will enrich future ex vivo human tissue research studies.
- |||||||||| Journal: Effect of transcription inhibition and generation of suppressive viral non-coding RNAs. (Pubmed Central) - Jul 19, 2019
Collectively, our results indicate that F07#13, which can terminate RNA Polymerase II at distinct sites, can generate scaffold RNAs, which may assemble into specific sets of "RNA Machines" that contribute to gene regulation. It remains to be seen whether these effects can also be seen in various clades that have varying promoter strength, mutant LTRs, and in patient samples.
- |||||||||| Journal: Autozygome and high throughput confirmation of disease genes candidacy. (Pubmed Central) - Jul 17, 2019
It remains to be seen whether these effects can also be seen in various clades that have varying promoter strength, mutant LTRs, and in patient samples. Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.
- |||||||||| apabetalone (RVX 208) / Resverlogix
Journal: BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency. (Pubmed Central) - Jul 13, 2019
The two BET inhibitors also reactivated HIV-1 transcription in cART treated patient-derived resting CD4+ T cells ex vivo, without influence on global immune cell activation. Our findings, in combination with previous reports, further confirm that BET inhibitors are a group of leading compounds for combating HIV-1 latency for viral eradication.
- |||||||||| dinaciclib (PS-095760) / Ligand, Merck (MSD)
Journal: Structure Based Design of Selective Non-covalent CDK12 Inhibitors. (Pubmed Central) - Jul 11, 2019
...Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]...This series of compounds inhibit phosphorylation of Ser2 on the C-terminal repeat domain of RNA pol II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.
- |||||||||| azacitidine / generics
Journal: Incorporation of novel agents into the treatment for acute myeloid leukemia (Pubmed Central) - Jul 6, 2019
In Japan, several new agents are also undergoing clinical trials, including Bcl-2 inhibitor venetoclax, CDK9 inhibitor alvocidib, smoothened (SMO) inhibitor glasdegib, hypomethylating agents guadecitabine and azacitidine, NEDD8 inhibitor pevonedistat, and FLT3 inhibitors quizartinib and gilteritinib. These agents will be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents or low-dose cytarabine to improve the therapeutic outcomes of AML.
- |||||||||| CT7001 / Carrick therapeutics
Journal: ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment. (Pubmed Central) - Jun 28, 2019
Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.
- |||||||||| Revlimid (lenalidomide) / BMS
Preclinical, Journal: Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. (Pubmed Central) - Jun 19, 2019
CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome...We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2;Flt3 AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.
- |||||||||| Review, Journal: NUT midline carcinoma of the head and neck: current perspectives. (Pubmed Central) - May 25, 2019
At the same time, combination approaches and novel targeted agents, such as next-generation BET inhibitors and CDK9 inhibitors, have shown preclinical activity. The present review explores the clinical pathological characteristics of NMC of the head and neck and presents the current state of the art on diagnosis, prognosis, and treatment of this rare but lethal disease.
- |||||||||| JQ-1 / Roche
Journal: A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter. (Pubmed Central) - May 22, 2019
...In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency...Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency.
- |||||||||| Journal: Small-molecule targeting of brachyury transcription factor addiction in chordoma. (Pubmed Central) - May 13, 2019
In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
- |||||||||| Biomarker, Review, Journal: CDK9 inhibitors in acute myeloid leukemia. (Pubmed Central) - May 11, 2019
Inhibition of CDK9 leads to downregulation of cell survival genes regulated by super enhancers such as MCL-1, MYC, and cyclin D1. As CDK9 inhibitors are nonselective, predictive biomarkers that may help identify patients most likely to respond to CDK9 inhibitors are now being utilized, with the goal of improving efficacy and safety.
- |||||||||| Thalomid (thalidomide) / Celgene, Fujimoto Pharma, SNS-032 / Sunesis
Journal: Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. (Pubmed Central) - May 7, 2019
Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
- |||||||||| Journal: CDK9: A Signaling Hub for Transcriptional Control. (Pubmed Central) - May 2, 2019
Here we provide a historical recount of CDK9 discovery and the current models suggesting CDK9 is a central hub necessary for proper execution of different steps in the transcription cycle. Finally, we discuss the current therapeutic strategies to treat CDK9 malfunction in several disease states.
- |||||||||| Journal: Roles of CDKs in RNA Polymerase II Transcription of the HIV-1 Genome. (Pubmed Central) - May 2, 2019
CDK8 may stimulate Pol II transcription of the HIV-1 genome through co-recruitment with NF-κB to the viral promoter. Some notable open questions are discussed concerning the roles of these CDKs in HIV-1 replication and viral latency.
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