Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7

Hu, Shanhu; Marineau, Jason; Rajagopal, Nisha; Hamman, Kristin B.; Choi, Yoojin; Schmidt, Darby; Ke, Nan Rosemary; Johannessen, Liv; Bradley, Michael J.; Orlando, David A.; Alnemy, Sydney; Ren, Yixuan; Ciblat, Stéphane; Winter, Dana K.; Kabro, Anzhelika; Sprott, Kevin T.; Hodgson, J. Graeme; Fritz, Christian; Carulli, John P.; Tomaso, Emmanuelle di; Olson, Eric R.

doi:10.1158/0008-5472.can-19-0119

Cited by 109 publications

(128 citation statements)

References 42 publications

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“…As a whole CDK7 inactivation dismantles two mechanisms needed for medulloblastoma proliferation and survival. These data are particularly relevant given the recent development of clinical grade CDK7 inhibitors (Hu et al, 2019a;Hu et al, 2019b;Patel et al, 2018). CDK7 inhibition with SY-5609 has already entered clinical trials (NCT04247126).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma

Veo

Danis

Pierce

et al. 2020

Preprint

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Myc-driven Medulloblastoma remains a major therapeutic challenge due to frequent metastasis and a poor 5-year survival rate. Myc gene amplification results in transcriptional dysregulation, proliferation, and survival of malignant cells. To identify therapeutic targets in Myc-amplified medulloblastoma we performed a CRISPR-Cas9 essentiality screen targeting 1140 genes annotated as the druggable genome. CDK7 was identified as a mediator of medulloblastoma tumorigenesis. Using covalent inhibitors and genetic depletion of CDK7 we observe the cessation of tumor growth in xenograft mouse models and increase in apoptotic mechanisms.The results are attributed to repression of a core set of Myc-driven transcriptional programs mediating DNA repair. We further establish that blocking CDK7 activity sensitizes cells to ionizing radiation leading to accrual of DNA damage and extended survival and tumor latency in medulloblastoma xenograft mouse models. Our studies establish a mechanism for selective inhibition of Myc-driven MB by CDK7 inhibition combined with radiation as a viable therapeutic strategy for Myc-amplified medulloblastoma.

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Section: Discussionmentioning

confidence: 99%

Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma

Veo

Danis

Pierce

et al. 2020

Preprint

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“…Critically, ovarian cancer oncogene CCNE1 was downregulated -2.0 and -2.2 fold following PAX8 and SOX17 depletion, respectively, consistent with CCNE1 being a target of these MTFs. Rb pathway alterations predict responses of patient derived xenograft models to SY-1365 (Hu et al, 2019), a covalent CDK7 inhibitor currently in clinical trials for advanced breast and ovarian cancer (NCT03134638). While we validated 3 factors in OV, additional MTFs may contribute to the transcriptional circuitry of HGSOC.…”

Section: Discussionmentioning

confidence: 99%

Predicting master transcription factors from pan-cancer expression data

Reddy

Fonseca

Fuente

et al. 2019

Preprint

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The function of critical developmental regulators can be subverted by cancer cells to control expression of oncogenic transcriptional programs. These "master transcription factors" (MTFs) are often essential for cancer cell survival and represent vulnerabilities that can be exploited therapeutically. The current approaches to identify candidate MTFs examine super-enhancer associated transcription factor-encoding genes with high connectivity in network models. This relies on chromatin immunoprecipitation-sequencing (ChIP-seq) data, which is technically challenging to obtain from primary tumors, and is currently unavailable for many cancer types and clinically relevant subtypes. In contrast, gene expression data are more widely available, especially for rare tumors and subtypes where MTFs have yet to be discovered. We have developed a predictive algorithm called CaCTS (Cancer Core Transcription factor Specificity) to identify candidate MTFs using pancancer RNA-sequencing data from The Cancer Genome Atlas. The algorithm identified 273 candidate MTFs across 34 tumor types and recovered known tumor MTFs. We also made novel predictions, including for cancer types and subtypes for which MTFs have not yet been characterized. Clustering based on MTF predictions reproduced anatomic groupings of tumors that share 1-2 lineage-specific candidates, but also dictated functional groupings, such as a squamous group that comprised five tumor subtypes sharing 3 common MTFs. PAX8, SOX17, and MECOM were candidate factors in high-grade serous ovarian cancer (HGSOC), an aggressive tumor type where the core regulatory circuit is currently uncharacterized. PAX8, SOX17, and MECOM are required for cell viability and lie proximal to super-enhancers in HGSOC cells. ChIPseq revealed that these factors co-occupy HGSOC regulatory elements globally and co-bind at critical gene loci including MUC16 (CA-125). Addiction to these factors was confirmed in studies using THZ1 to inhibit transcription in HGSOC cells, suggesting early down-regulation of these genes may be responsible for cytotoxic effects of THZ1 on HGSOC models. Identification of MTFs across 34 tumor types and 140 subtypes, especially for those with limited understanding of transcriptional drivers paves the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

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“…There is one CDK-inhibitor (SY-1365) in phase I clinical trial for ovarian and breast cancer (Hu et al, 2019). The inhibition with SY-1365 leads to decreased levels of multiple oncogenic transcription factors and it exhibits the inhibitory effects on multiple cancer cell lines at nanomolar level.…”

Section: Inhibitors Of Transcription Factor Gene Expressionmentioning

confidence: 99%

“…The inhibition with SY-1365 leads to decreased levels of multiple oncogenic transcription factors and it exhibits the inhibitory effects on multiple cancer cell lines at nanomolar level. In addition, mouse xenograft studies showed modest antitumor activity in both AML as well as ovarian cancer, and a synergistic effect with venetoclax (Hu et al, 2019).…”

Section: Inhibitors Of Transcription Factor Gene Expressionmentioning

confidence: 99%

Transcription and Translation Inhibitors in Cancer Treatment

et al. 2020

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Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

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Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7

Cited by 109 publications

References 42 publications

Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma

Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma

Predicting master transcription factors from pan-cancer expression data

Transcription and Translation Inhibitors in Cancer Treatment

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