2. Academic Validation
  3. The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis

The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis

  • Biomed Pharmacother. 2024 Jun:175:116705. doi: 10.1016/j.biopha.2024.116705.
Yao Yao Yan 1,  Yu Meng Wang 1,  Jun Hao Shen 1,  Yu Jie Jian 1,  Cen Cen Lei 1,  Quan Wang 1,  Chao Liu 2,  Xing Xing Zhang 3,  Xin Hua Liu 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, PR China.
  • 2 School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China; Anhui Key Laboratory of Spin Electron and Nanomaterials, Suzhou 234000, PR China; School of Chemistry and Chemical Engineering, Suzhou University, Suzhou 234000, PR China. Electronic address: ahliuchao333@163.com.
  • 3 School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, PR China. Electronic address: xxzhangahmu@163.com.
  • 4 School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, PR China; School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China. Electronic address: xhliuhx@163.com.
PMID: 38713949 DOI: 10.1016/j.biopha.2024.116705
Abstract

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 Inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 Enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Keywords

CDK8 inhibitor; Design; Psoriasis activity; Pyrrolo-pyridine.

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