Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7

Marineau, Jason; Hamman, Kristin B.; Hu, Shanhu; Alnemy, Sydney; Mihalich, Janessa; Kabro, Anzhelika; Whitmore, Kenneth Matthew; Winter, Dana K.; Roy, Stéphanie; Ciblat, Stéphane; Ke, Nan Rosemary; Savinainen, Anneli; Wilsily, Ashraf; Malojcic, G.; Zahler, Robert; Schmidt, Darby; Bradley, Michael J.; Waters, Nigel J.; Chuaqui, Claudio

doi:10.1021/acs.jmedchem.1c01171

Cited by 47 publications

(31 citation statements)

References 24 publications

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“…Of note, two selective CDK7 inhibitors, SY-5609 and CT7001, (ICEC9042) are currently investigated in clinical studies. Both inhibitors are tested as single agents and in combination with standard therapy in different tumor types [ 67 , 68 , 69 ]. In light of our data, we believe it worthwhile to test the drugs on TGCT as well.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

Funke

Düster

Wilson

et al. 2022

Cancers

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Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. 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.

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Section: Discussionmentioning

confidence: 99%

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

Funke

Düster

Wilson

et al. 2022

Cancers

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“…The incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped to achieve the required potency and metabolic stability. SY-5609 exhibits potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models at doses as low as 2 mg/kg [ 102 ].…”

Section: Development Of Selective Cdk Inhibitorsmentioning

confidence: 99%

The Renaissance of Cyclin Dependent Kinase Inhibitors

Ettl

Schulz

Bauer

2022

Cancers

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Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.

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Section: Rationale For Targeting Tcdks In Crpcmentioning

confidence: 99%

“…Recently, Syros Pharmaceuticals have announced the clinical development of a new orally available ATP-competitive CDK7 inhibitor, SY-5609 [ 70 ], after terminating previous studies using the covalent compound SY-1365 [ 71 ]. Preclinically, SY-5609 presents with favourable antitumor activity in ER-positive breast cancer [ 72 ], TNBC and ovarian cancer models [ 70 ]. It is currently being assessed in a phase I dose-escalation study (NCT04247126) in patients with advanced solid tumours, with the most recent update from the company reporting good clinical activity.…”

Section: Rationale For Targeting Tcdks In Crpcmentioning

confidence: 99%

Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer

et al. 2022

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Transcriptional deregulation has emerged as a hallmark of several cancer types. In metastatic castration-resistant prostate cancer, a stage in which systemic androgen deprivation therapies fail to show clinical benefit, transcriptional addiction to the androgen receptor is maintained in most patients. This has led to increased efforts to find novel therapies that prevent oncogenic transactivation of the androgen receptor. In this context, a group of druggable protein kinases, known as transcription associated cyclin-dependent kinases (tCDKs), show great potential as therapeutic targets. Despite initial reservations about targeting tCDKs due to their ubiquitous and prerequisite nature, preclinical studies showed that selectively inhibiting such kinases could provide sufficient therapeutic window to exert antitumour effects in the absence of systemic toxicity. As a result, several highly specific inhibitors are currently being trialled in solid tumours, including prostate cancer. This article summarises the roles of tCDKs in regulating gene transcription and highlights rationales for their targeting in prostate cancer. It provides an overview of the most recent developments in this therapeutic area, including the most recent clinical advances, and discusses the utility of tCDK inhibitors in combination with established cancer agents.

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Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7

Cited by 47 publications

References 24 publications

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

The Renaissance of Cyclin Dependent Kinase Inhibitors

Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer

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