Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer,The Prostate

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Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer
The Prostate ( IF 2.6 ) Pub Date : 2023-08-09 , DOI: 10.1002/pros.24606
John T Isaacs _{1,

2,

3} , Susan L Dalrymple ₁ , Lizamma Antony ₁ , David Marc Rosen ₁ , Ilsa M Coleman ₄ , Peter S Nelson ₄ , Maya Kostova ₁ , Iain A Murray ₅ , Gary H Perdew ₅ , Samuel R Denmeade _{1,

2,

3} , Emmanuel S Akinboye ₁ , W Nathaniel Brennen _{1,

2,

3}

Affiliation

The quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival.

中文翻译：

用于转移性去势抵抗性前列腺癌的 HDAC4、HIF-1α 和 MEF-2 信号传导的第三代喹啉-3-甲酰胺转录干扰剂

喹啉-3-甲酰胺 Tasquinimod (TasQ) 是一种口服活性维持疗法，通过与 HDAC4 变构结合发挥靶向作用机制。这可以防止 HDAC4/NCoR1/HDAC3 复合物的形成，破坏 HIF-1α 转录激活并抑制受损肿瘤微环境中适应性生存信号传导所需的 MEF-2 靶基因。在针对转移性去势抵抗性前列腺癌 (mCRPC) 的 3 期临床试验中，TasQ（1 毫克/天）可延长进展时间，但不会延长总生存期。

更新日期：2023-08-09

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