Discovery of a novel oral type Ⅰ CDK8 inhibitor against acute myeloid leukemia

Eur J Med Chem. 2023 May 5:251:115214. doi: 10.1016/j.ejmech.2023.115214. Epub 2023 Feb 24.

Abstract

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 Ⅰ 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.

Keywords: AML; CDK8 inhibitor; STAT-1; STAT-5; pyrrolo[2,3-b]pyridine.

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase 8
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Antineoplastic Agents
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8