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.
Xing Xing Zhang  1 ,  Yao Yao Yan  1 ,  Xiao Ma  2 ,  Yun Xiao  1 ,  Cen Cen Lei  1 ,  Yu Meng Wang  1 ,  Chao Liu  3 ,  Quan Wang  1 ,  Xing Tao Zhang  4 ,  Wen Dan Cheng  5 ,  Xin Hua Liu  6
Affiliations
  • 1. School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
  • 2. Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China.
  • 3. School of Biological and Food Engineering, Suzhou University, Suzhou, 234000, PR China.
  • 4. School of Biological and Food Engineering, Suzhou University, Suzhou, 234000, PR China. Electronic address: [email protected].
  • 5. Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China. Electronic address: [email protected].
  • 6. School of Biological and Food Engineering, Suzhou University, Suzhou, 234000, PR China; School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. Electronic address: [email protected].
PMID: 36889252 DOI: 10.1016/j.ejmech.2023.115214
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.
Products