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 57â¯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.
Subject(s)
Cyclin-Dependent Kinase 8 , Protein Kinase Inhibitors , Psoriasis , Animals , Cyclin-Dependent Kinase 8/antagonists & inhibitors , Cyclin-Dependent Kinase 8/metabolism , Psoriasis/drug therapy , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Mice , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Pyridines/pharmacology , Pyridines/chemistry , Mice, Inbred BALB C , Interleukin-10/metabolism , Male , Pyrroles/pharmacology , Pyrroles/chemistry , Forkhead Transcription Factors/metabolism , Drug Discovery/methods , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Disease Models, Animal , Skin/drug effects , Skin/pathology , Skin/metabolismABSTRACT
CDK8 plays a key role in acute myeloid leukemia, colorectal cancer and other cancers. Here, a total of 54 compounds were designed and synthesized. Among them, the most potent one compound 43 (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide), a novel CDK8 â inhibitor, showed strong inhibitory activity against CDK8 (IC50 = 51.9 nM), good kinase selectivity, good anti AML cell proliferation activity (molm-13 GC50 = 1.57 ± 0.59 µM) and low toxicity in vivo (acute toxicity: 2000 mg/kg). Further mechanistic studies revealed that this compound could target CDK8 and then phosphorylate STAT-1 and STAT-5 thereby inhibiting of AML cell proliferation. In addition, compound 43 showed relatively good bioavailability (F = 28.00%) and could inhibit the growth of AML tumors in a dose-dependent manner in vivo. This study facilitates the further development of more potent CDK8 inhibitors for the treatment of the AML.
