Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation

Yu, Mingfeng; Teo, Theodosia; Yang, Yuchao; Li, Manjun; Yi, Long; Philip, Stephen; Noll, Benjamin; Heinemann, Gary; Diab, Sarah; Eldi, Preethi; Mekonnen, Laychiluh; Anshabo, Abel Tesfaye; Rahaman, Muhammed H.; Milne, Robert; Hayball, John D.; Wang, Shudong

doi:10.1016/j.ejmech.2021.113248

Cited by 14 publications

(8 citation statements)

References 57 publications

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“…White solid: 64%. [2,3-b]pyridin-5-yl)phenyl)-N- (3-fluoro-4methylphenyl)propenamide (21). White solid: 63%.…”

Section: T H I S C O N T E N T I S O N L Y L I C E N S E D F O R C O ...mentioning

confidence: 99%

“…Cyclin-dependent kinase 8 (CDK8), a member of the CDK family, which is a group of serine/threonine protein kinases, was defined as a substance that plays a vital role in regulating transcription and as a key oncogenic driver in many cancers, such as melanoma, , prostate cancer, , CRC, ,− breast cancer, ,, and acute myeloid leukemia. − Therefore, it is believed that CDK8 may be suitable as a potential therapeutic target, ,, but no CDK8 inhibitors were approved for marketing so far. Furthermore, except for TSN-084 (NCT05300438), a type II multikinase inhibitor with targets such as CDK8/19, c-MET, FLT3, and TRK, until now, no type II CDK8 inhibitors entered the clinical study. , It has been confirmed that CDK8 is a CRC oncogene that could regulate β-catenin activity to inhibit the WNT/β-catenin signal for treatment of colorectal cancer. − Many CDK8 inhibitors reflected good activity in xenografts of CRC cells, but not further studied due to toxicity, such as CCT251921, CCT-251545, and MSC25308186 − (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of the Novel 1H-Pyrrolo[2,3-b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer

et al. 2022

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Few targeted drugs were approved for treatment of colorectal cancer (CRC). Cyclin-dependent kinase 8 played a vital role in regulating transcription and was a key colorectal oncogene associated to colorectal cancer. Here, through de novo drug design and in depth structure–activity relationship analysis, title compound 22, (3-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 inhibitor, which exhibited potent kinase activity with an IC50 value of 48.6 nM and could significantly inhibit tumor growth in xenografts of CRC in vivo. Further mechanism studies indicated that it could target CDK8 to indirectly inhibit β-catenin activity, which caused downregulation of the WNT/β-catenin signal and inducing cell cycle arrest in G2/M and S phases. More importantly, the title compound exhibited low toxicity with good bioavailability (F = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal cancer.

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“…White solid: 64%. [2,3-b]pyridin-5-yl)phenyl)-N- (3-fluoro-4methylphenyl)propenamide (21). White solid: 63%.…”

Section: T H I S C O N T E N T I S O N L Y L I C E N S E D F O R C O ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of the Novel 1H-Pyrrolo[2,3-b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer

et al. 2022

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“…More importantly, in 2019, SEL120-34A was approved for clinical trials for treatment of advanced AML (NCT04021368) 18 . In addition, many CDK8 inhibitors were also reported to have good anti proliferative activity on AML cells 10–12 , 19–22 , such as cortistatinA 10 , AU1-100 11 , MK-256 12 , etc ( Figure 1 ). Although, three CDK8 inhibitors, such as BCD-115 (NCT03065010), SEL120-34A (NCT04021368, NCT05052255) and TSN-084 (NCT05300438) have been approved for clinical trials, however, due to toxicity and drug PK efficacy, there are no commercially available drugs on the market.…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia

Chen,

Wang,

Yan

et al. 2024

Journal of Enzyme Inhibition and Medicinal Chemistry

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It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 ( 3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide ) showed the most potent inhibiting activity against CDK8 with an IC 50 value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC 50 = 0.02 ± 0.01 μ M, MV4-11 GC 50 = 0.03 ± 0.01 μ M). Mechanistic studies revealed that this compound 12 could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound 12 showed relative good bioavailability ( F = 38.80%) and low toxicity in vivo . This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

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“…In contrast, CDK8 overexpression produces tumor suppressive effects of cancers promoted by Notch or EGFR signaling ( 27 ). The significance of alterations in mediator kinase components and cancer progression has spurned the development of specific CDK8/19 inhibitors ( 28 – 30 ), several of which are in clinical trials for ER-positive breast cancers and acute myeloid leukemia ( 31 ). Despite that HIV-1 expression is regulated by at least three factors whose activity is controlled by CDK8, TCF/LEF, NFκB, and STAT1/3, the role of CDK8/19 and the kinase module for regulation of HIV-1 provirus expression and response to T cell signaling has not been characterized.…”

Section: Introductionmentioning

confidence: 99%

CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells

Horvath,

Brumme,

Sadowski

2023

J Virol

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Latent HIV-1 provirus represents the barrier toward a cure for infection and is dependent upon the host RNA Polymerase (Pol) II machinery for reemergence. Here, we find that inhibitors of the RNA Pol II mediator kinases CDK8/19, Senexin A and BRD6989, inhibit induction of HIV-1 expression in response to latency-reversing agents and T cell signaling agonists. These inhibitors were found to impair recruitment of RNA Pol II to the HIV-1 LTR. Furthermore, HIV-1 expression in response to several latency reversal agents was impaired upon disruption of CDK8 by shRNA or gene knockout. However, the effects of CDK8 depletion did not entirely mimic CDK8/19 kinase inhibition suggesting that the mediator kinases are not functionally redundant. Additionally, treatment of CD4 + peripheral blood mononuclear cells isolated from people living with HIV-1 and who are receiving antiretroviral therapy with Senexin A inhibited induction of viral replication in response to T cell stimulation by PMA and ionomycin. These observations indicate that the mediator kinases, CDK8 and CDK19, play a significant role for regulation of HIV-1 transcription and that small molecule inhibitors of these enzymes may contribute to therapies designed to promote deep latency involving the durable suppression of provirus expression. IMPORTANCE A cure for HIV-1 infection will require novel therapies that can force elimination of cells that contain copies of the virus genome inserted into the cell chromosome, but which is shut off, or silenced. These are known as latently-infected cells, which represent the main reason why current treatment for HIV/AIDS cannot cure the infection because the virus in these cells is unaffected by current drugs. Our results indicate that chemical inhibitors of Cdk8 also inhibit the expression of latent HIV provirus. Cdk8 is an important enzyme that regulates the expression of genes in response to signals to which cells need to respond and which is produced by a gene that is frequently mutated in cancers. Our observations indicate that Cdk8 inhibitors may be employed in novel therapies to prevent expression from latent provirus, which might eventually enable infected individuals to cease treatment with antiretroviral drugs.

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Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation

Cited by 14 publications

References 57 publications

Discovery of the Novel 1H-Pyrrolo[2,3-b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer

Discovery of the Novel 1H-Pyrrolo[2,3-b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer

Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia

CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells

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