Synthesis and Evaluation of a Novel Series of Diphenylamine and Diphenylether Derivatives with Osteoblastogenic and Osteogenic Effects &lt;i&gt;via&lt;/i&gt; CDK8 Inhibition

Morishita, Ko; Yamamoto, Megumi; Takashima, Shunsuke; Ando, Masafumi; Kawai, Shota; Otake, Kazuya; Shoji, Yoshimichi; Hinoi, Eiichi; Kitao, Tatsuya; Shirahase, Hiroaki

doi:10.1248/cpb.c24-00392

Chem. Pharm. Bull.

2024

DOI: 10.1248/cpb.c24-00392

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Synthesis and Evaluation of a Novel Series of Diphenylamine and Diphenylether Derivatives with Osteoblastogenic and Osteogenic Effects <i>via</i> CDK8 Inhibition

Ko Morishita,

Megumi Yamamoto,

Shunsuke Takashima

et al.

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2024

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Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming

Khadka,

Lukas,

Sun

et al. 2024

Preprint

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Uterine fibroids (UFs) are the most common non-cutaneous tumors in women worldwide. UFs arise from genetic alterations in myometrial stem cells (MM SCs) that trigger their transformation into tumor initiating cells (UF SCs). Mutations in the RNA polymerase II Mediator subunit MED12 are dominant drivers of UFs, accounting for 70% of these clinically significant lesions. Biochemically, UF driver mutations in MED12 disrupt CDK8/19 kinase activity in Mediator, but how Mediator kinase disruption triggers MM SC transformation remains unknown. Here, we show that pharmacologic inhibition of CDK8/19 in MM SCs removes a barrier to myogenic differentiation down an altered pathway characterized by molecular phenotypes characteristic of UFs, including oncogenic growth and extracellular matrix (ECM) production. These perturbations appear to be induced by transcriptomic changes, arising in part through epigenomic alteration and super-enhancer reprogramming, that broadly recapitulate those found in MED12-mutant UFs. Altogether these findings provide new insights concerning the biological role of CDK8/19 in MM SC biology and UF formation.

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Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming

Khadka,

Lukas,

Sun

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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Synthesis and Evaluation of a Novel Series of Diphenylamine and Diphenylether Derivatives with Osteoblastogenic and Osteogenic Effects <i>via</i> CDK8 Inhibition

Cited by 1 publication

References 24 publications

Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming

Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming

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